Showing that a new molecular entity does not cause clinically relevant QTc prolongation is required in nearly every small-molecule development program. It also shapes phase 1 design, ECG collection plans, and labeling. Since the ICH E14/S7B Q&A revisions, sponsors can choose among several routes: a dedicated thorough QT study, concentration-QTc modeling of phase 1 data, an integrated nonclinical-clinical package, or a justified waiver. The route a team picks affects its timeline and budget, and it determines whether FDA is likely to require postmarketing work.
The analysis below reviews FDA NME NDA approvals from September 2021 through September 2026. Each application is classified by the QT assessment approach it used and by FDA's stated conclusion. The classifications come from Section 12.2 of the approved labeling and from the clinical pharmacology and QT-IRT reviews. The analysis also flags the applications where FDA accepted evidence short of a thorough QT study, and the conditions attached to that acceptance.
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QTc characterization for FDA NME approvals, Sept 2021 to Sept 2026
Scope: 166 distinct NME NDAs (original applications, chemical type 1 or 1/4) with Drugs@FDA decision dates from 2021-09-28 to 2026-09-28. Therapeutic protein BLAs were excluded because ICH E14 Q&A treats large targeted proteins and monoclonal antibodies as not needing a TQT study absent a specific signal 1219. Classification was extracted from the approved label (section 12.2) and FDA review documents (clinical pharmacology and QT-IRT reviews) for each application; each cell carries the source citation.
Tally by approach and outcome
| Approach | N | No clinically relevant prolongation | QTc prolongation identified | Not adequately characterized | Unknown |
|---|---|---|---|---|---|
| Dedicated TQT study | 67 | 58 | 9 | 0 | 0 |
| C-QTc from phase 1 healthy-volunteer data (TQT substitute) | 28 | 19 | 5 | 4 | 0 |
| C-QTc / ECG analysis in patient studies (alternative QT study) | 29 | 0 | 11 | 18 | 0 |
| Integrated nonclinical + clinical assessment | 18 | 18 | 0 | 0 | 0 |
| Routine ECG monitoring only | 7 | 3 | 0 | 4 | 0 |
| Not evaluated / waived | 14 | 6 | 0 | 6 | 2 |
| Not found in retrieved documents | 3 | 0 | 0 | 0 | 3 |
| Total | 166 | 104 | 25 | 32 | 5 |
Outcomes follow one rule, applied in order. "QTc prolongation identified": the label states the drug causes QTc prolongation, or an upper 90% confidence bound reached 10 ms or more at a tested exposure (unless FDA called that estimate inconclusive). "Not adequately characterized": otherwise, FDA excluded only a large (≥20 ms) mean effect, declined to conclude there is no QTc effect, or required a postmarketing QT study. "No clinically relevant prolongation": everything else.
Dedicated TQT study (67)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Qulipta (atogepant) | 215206, 2021-09-28 219 | The study tested a single 300-mg dose—5 times the maximum recommended daily dose (60 mg QD). This covered the high clinical-exposure scenario for 60 mg QD, specified as 2.2-fold Cmax with a strong CYP3A4 inhibitor or OATP inhibitor. 300 | At 300 mg, the FDA by-time analysis showed a placebo-adjusted change in QTcF of 1.2 ms at 24 hours (90% CI: -1.0 to 3.2 ms); thus, the upper bound was below 10 ms. The review states that the 10-ms threshold was excluded at the supratherapeutic dose. 300 | No clinically relevant prolongation | |
| Tavneos (avacopan) | 214487, 2021-10-07 208 | The therapeutic dose was 30 mg twice daily. Avacopan 100 mg twice daily for 7 days produced geometric-mean Cmax ~780 ng/mL, approximately a 2-fold margin over the expected steady-state Cmax (~350 ng/mL) at the maximum therapeutic dose and covered the stated worst-case exposure scenario (CYP3A inhibition). 642 | At 100 mg twice daily (Cmax 779.8 ng/mL), FDA concentration–QTc analysis estimated ΔΔQTcF 0.8 ms, with 90% CI −2.8 to 4.5 ms. The sponsor's model similarly estimated 0.82 ms (upper CI 4.05 ms) and stated that a QTc effect >10 ms could be excluded over observed avacopan/M1 concentrations up to ~1,220/~335 ng/mL. 643 | No clinically relevant prolongation | Not applicable to the final approval assessment because a dedicated TQT study was conducted. Earlier phase-1/food-effect/cardiac-safety Study CL007 had been considered as a possible TQT substitute, but FDA later found it inadequate because it lacked a placebo control and separate positive control and did not provide sufficient high-exposure margin; a separate study was requested. The review also notes formulation limitations: higher exposure was difficult to achieve because PEG-4000 at high oral doses could cause diarrhea. 646 |
| Livtencity (maribavir) | 215596, 2021-11-23 215 | The supratherapeutic 1,200-mg dose produced a Cmax approximately 2-fold higher than that at the recommended 400-mg dose. 281 | No significant QT prolongation was detected with maribavir 100 mg or 1,200 mg. The largest upper bounds of the two-sided 90% CIs for mean placebo-adjusted QT effects were below 10 ms. At 1,200 mg, the maximum mean QT change was 2.3 ms (90% CI: -0.1 to 4.7 ms). 281 | No clinically relevant prolongation | |
| Leqvio (inclisiran sodium) | 214012, 2021-12-22 226 | The 900-mg single dose (three SC injections) was 3 times the maximum recommended dose and covered the worst-case renal-impairment exposure scenario. Mean Cmax was about 2,888–2,890 ng/mL versus 509 ng/mL at the therapeutic dose in healthy subjects and 1,760 ng/mL in severe renal impairment. Thus, the study exposure exceeded anticipated therapeutic exposure; the maximum observed individual concentration was 8,430 ng/mL. 543 | At 4 hours, FDA by-time analysis estimated ΔΔQTcF of 2.9 ms (90% CI, 0.5 to 5.2 ms), excluding the 10-ms threshold. No participant given 900 mg had QTcF >480 ms or ΔQTcF >30 ms. Supportive concentration-QTc modeling predicted ΔΔQTcF 1.9 ms (90% CI, 0.6 to 3.2 ms) at the mean study Cmax; at the maximum individual concentration, the predicted effect was 5.7 ms (90% CI, 1.1 to 10.3 ms). 543 | No clinically relevant prolongation | Not applicable to the approval assessment: although the sponsor initially sought a thorough-QT waiver based on inclisiran's large molecular size, short half-life, low systemic exposure, and lack of accumulation, FDA denied the waiver request and required QTc characterization. A dedicated thorough-QT study was subsequently conducted. 546 |
| Quviviq (daridorexant hydrochloride) | 214985, 2022-01-07 222 | The maximum recommended dose was 50 mg once daily; the 200-mg supratherapeutic dose was 4 times that dose. FDA concluded this highest dose covered the high clinical-exposure scenario (CYP3A inhibition and hepatic impairment). QTc results were evaluated across concentrations up to 3,030 ng/mL. 342 | The primary model-based analysis found mean model-predicted ΔΔQTcF and its 90% CI were below 10 ms throughout the evaluated concentration range (up to 3,030 ng/mL). At 50 mg, mean ΔΔQTcF was 1.40 ms (90% CI 0.48–2.32); at 200 mg, 1.84 ms (90% CI −0.12 to 3.79). FDA's exposure-response analysis at the 200-mg mean concentration (1,809.2 ng/mL) estimated 0.5 ms (90% CI −1.8 to 2.9). 342 | No clinically relevant prolongation | Not applicable: FDA had indicated that a thorough-QT study was needed, and the sponsor agreed to conduct one. Although the sponsor’s moxifloxacin by-time profile deviated from the historic profile because dosing occurred at nighttime, FDA performed a QT-bias analysis and found no significant bias; assay sensitivity was established by the moxifloxacin arm. 346 |
| Cibinqo (abrocitinib) | 213871, 2022-01-14 227 | The 600-mg single dose was 3 times the maximum approved recommended dose (200 mg) and covered the highest clinical exposure scenario—2.5-fold increased exposure with CYP2C19 inhibition. The review also states the observed Cmax of 1,890 ng/mL provided approximately a 1.7-fold margin over the 200-mg steady-state target-population Cmax of 1,123 ng/mL; because 100 mg was recommended for approval, the margin would be larger. 562 | FDA exposure-response analysis at abrocitinib 600 mg and concentration 1,891 ng/mL estimated ΔΔQTcF of 5.3 ms, with a 90% CI of 3.9 to 6.7 ms (upper bound <10 ms). No subject in the 600-mg group had QTcF >480 ms with ΔQTcF >30 ms. 556 | No clinically relevant prolongation | No standard assessment was waived: a dedicated thorough-QT study was conducted. Although the IRT proposed Section 12.2 wording that, at 1.5 times the maximum approved recommended dose, the drug does not prolong QT to a clinically relevant extent, the approval review states that no QT language was needed in the label. 560 |
| Vivjoa (oteseconazole) | 215888, 2022-04-26 211 | The highest regimen was 600 mg daily on Days 1-13 plus 1200 mg on Day 14, producing Cmax 12,597 ng/mL—approximately 4.7-fold (described elsewhere as ~5-fold) the maximum therapeutic Cmax of approximately 2,679.3 ng/mL under the recommended regimen. This was expected to cover worst-case exposure, including renal impairment. 292 | At 12,597.1 ng/mL on Day 14, the concentration-QTcF model predicted a mean placebo-corrected change from baseline (ΔΔQTcF) of -5.6 ms, with 90% CI -10.5 to -0.8 ms; thus, the upper bound was -0.8 ms. No subjects had observed QTcF >450 ms or a QTcF increase from baseline >60 ms after oteseconazole. 290 | No clinically relevant prolongation | |
| Voquezna Triple Pak (amoxicillin; clarithromycin; vonoprazan fumarate) | 215152, 2022-05-03 220 | The highest studied dose was single-dose vonoprazan 120 mg—six times the maximum recommended dose—and it covered the stated worst-case exposure scenario, because severe renal and hepatic impairment increase vonoprazan Cmax by approximately 80%. 650 | FDA by-time analysis: at 8 hours, ΔΔQTcF was 2.2 ms (90% CI 0.4–4.1) with 40 mg and 3.9 ms (90% CI 2.0–5.7) with 120 mg; thus, the upper 90% CI was below 10 ms at both doses. The reviewer’s concentration-QTc analysis predicted ΔΔQTcF at mean Cmax of 0.4 ms (90% CI −0.1 to 0.8) for 40 mg and −0.7 ms (90% CI −1.8 to 0.5) for 120 mg. 651 | No clinically relevant prolongation | |
| Sotyktu (deucravacitinib) | 214958, 2022-09-09 236 | The highest TQT dose was 36 mg single dose (6× the 6-mg once-daily recommended dose), with geometric-mean Cmax about 315 ng/mL versus about 45 ng/mL at steady state with 6 mg once daily—approximately a 7-fold Cmax margin. FDA stated that 36 mg covered the high clinical-exposure scenario of hepatic impairment. 462 | At deucravacitinib 36 mg (concentration 315 ng/mL), FDA’s exposure-response analysis estimated placebo-adjusted change from baseline QTcF (ΔΔQTcF) of 2.3 ms, with 90% CI 1.4 to 3.2 ms. The sponsor model estimated 2.1 ms (upper CI 3.19 ms) at 36 mg; by-time analyses had largest upper confidence bounds below 10 ms for both 12 mg and 36 mg. No subject had QTcF >450 ms or ΔQTcF >30 ms in the reported categorical analysis. 459 | No clinically relevant prolongation | |
| Elucirem (gadopiclenol) | 216986, 2022-09-21 232 | The recommended dose is 0.05 mmol/kg. The highest TQT dose, 0.3 mmol/kg IV, was 6 times the recommended dose and produced geometric-mean Cmax of approximately 2,491 µg/mL. This dose was considered to cover the clinically relevant worst-case exposure scenario of renal impairment. 520 | No significant QTc-prolongation effect was detected. FDA central-tendency results were ΔΔQTcF 5.1 ms (90% CI 3.2–7.0) at 0.3 mmol/kg and 2.1 ms (90% CI 0.2–4.0) at 0.1 mmol/kg. Exposure-response modeling predicted ΔΔQTcF of 2.23 ms, with upper confidence interval 3.26 ms, at the mean peak concentration for 0.3 mmol/kg. 519 | No clinically relevant prolongation | |
| Lytgobi (futibatinib) | 214801, 2022-09-30 237 | The approved recommended dose was 20 mg once daily. The study evaluated 20 mg and a supratherapeutic 80-mg single dose (4 times the recommended dose), with the 80-mg dose providing approximately 4-fold the RP2D Cmax. 891 | At 20 mg and 80 mg, the upper bound of the 90% confidence interval for QTc effect was <5 ms. By-time analysis excluded the 10-ms threshold at both doses. Exposure-response modeling predicted ΔΔQTcF of 1.08 ms (upper confidence interval 1.94 ms) at the mean 80-mg Cmax (~542 ng/mL), and 1.06 ms (upper confidence interval 1.48 ms) at the mean 20-mg Cmax (~165 ng/mL). 896 | No clinically relevant prolongation | |
| Sunlenca (lenacapavir sodium) | 215974, 2022-12-22 230 | Supratherapeutic lenacapavir exposures were 9-fold higher than therapeutic SUNLENCA exposures. 2710 2710 | At 9-fold supratherapeutic exposure, SUNLENCA did not prolong QTcF to any clinically relevant extent. 2710 2710 | No clinically relevant prolongation | |
| Brenzavvy (bexagliflozin) | 214373, 2023-01-20 262 | The studied 100-mg single dose was 5 times the 20-mg recommended dose. Its mean Cmax was 1,276 ng/mL, versus 176 ng/mL at the stated highest clinical-exposure scenario (20 mg with food), providing 7.25-fold Cmax coverage. 834 | The largest observed upper bound of the two-sided 90% CI for placebo-corrected change in QTcF was 4.2 ms (point estimate 2.4 ms at 10 hours), below the 10-ms regulatory-concern threshold. Moxifloxacin assay sensitivity was demonstrated: ΔΔQTcF 13.5 ms, 90% CI 10.5–16.5 ms at 3 hours. 835 | No clinically relevant prolongation | |
| Jaypirca (pirtobrutinib) | 216059, 2023-01-27 254 | Pirtobrutinib 900 mg as a single dose (4.5 times the 200-mg recommended dose) produced Cmax about 14,280 ng/mL, approximately 2.1-fold the steady-state Cmax at 200 mg once daily (6,460 ng/mL). The review noted residual uncertainty whether this covered steady-state exposure in severe hepatic impairment, because that study was pending. 871 | At the mean peak concentration after 900 mg (14,280 ng/mL), FDA exposure-response analysis estimated placebo-corrected ΔΔQTcF of 0.7 ms, with 90% CI −1.2 to 2.6 ms. The largest by-time upper bound of the 90% CI was also <10 ms. No participant had QTcF ≥450 ms or a QTcF increase >30 ms after 900 mg. 872 | No clinically relevant prolongation | Not waived: a dedicated TQT study was conducted. Its exposure coverage was potentially limited for severe hepatic impairment because the hepatic-impairment study was pending, so it was unclear whether the TQT study covered steady-state Cmax in patients with severe hepatic impairment at the approved dose without dose reduction. 872 |
| Jesduvroq (daprodustat) | 216951, 2023-02-01 184 | The supratherapeutic 500-mg single dose was 10 times the maximum recommended dose (the review identifies 48 mg as the maximum recommended dose in dialysis-dependent CKD). FDA stated that this exposure covered the anticipated high clinical-exposure scenario with CYP2C8 inhibition; 500 mg was also the highest single oral dose evaluated in healthy adults. 978 | No significant QTc-prolongation effect was detected in the TQT study at 75 mg or 500 mg. The available rows do not provide a numerical mean QTc effect or 90% confidence-interval upper bound. 977 | No clinically relevant prolongation | |
| Filspari (sparsentan) | 216403, 2023-02-17 192 | The therapeutic 800-mg single dose produced mean Cmax 8.2 µg/mL, similar to steady-state Cmax 7.1 µg/mL with 400 mg once daily. The 1600-mg single dose produced mean Cmax 11.6 µg/mL and covered 1.2-fold the high clinical-exposure scenario (CYP3A inhibition). 990 | The label reports maximal mean QTcF effects of 8.8 ms (90% CI, 5.9 to 11.8) at 800 mg and 8.1 ms (90% CI, 5.2 to 11.0) at 1600 mg. Thus, the upper bounds exceeded 10 ms, but neither dose had an upper 90% CI bound near 20 ms. The effect was not dose-dependent and showed a delay relative to peak sparsentan concentrations. 991 | QTc prolongation identified | A standard dedicated assessment was not waived: it was a TQT study. The C-QTc modeling was limited/not used for regulatory interpretation because there was approximately a 1-hour delay between Cmax and maximal mean ΔΔQTcF, QT effects were similar despite higher concentrations at 1600 mg than 800 mg, and the concentration-QTc relationship did not meet linearity/hysteresis assumptions. Supporting nonclinical findings were a hERG safety margin >2912-fold and no QTc prolongation in telemetry monkeys at 6.2-fold anticipated high clinical exposure. 987 |
| Skyclarys (omaveloxolone) | 216718, 2023-02-28 187 | The completed assessment used 450 mg with a high-fat meal in healthy subjects—3 times the recommended 150-mg dose. The provided documents do not report a plasma exposure multiple versus the maximum clinical exposure for this study. 939 | The label reports that clinically significant QTc interval prolongation was not observed. A numerical mean QTc effect or 90% CI upper bound is not provided in the retrieved rows. 939 | No clinically relevant prolongation | The original submission’s clinical ECG studies lacked a positive control, did not assess high clinical exposures, did not collect high-quality digital ECGs, and did not time ECGs to capture effects at maximum omaveloxolone concentrations. Nonclinical hERG and in-vivo QTc studies also did not meet best practices and could not support an integrated nonclinical assessment. Thus, FDA required the postmarketing TQT study to exclude mean QTc effects >10 ms. 927 |
| Daybue (trofinetide) | 217026, 2023-03-10 179 | The highest evaluated dose was 24 g single dose. Its observed mean Cmax was 196 µg/mL, considered adequate to cover the anticipated maximum clinical exposure of 203 µg/mL (approximately 0.97×). However, it did not cover the predicted high-exposure renal-impairment scenario: ESRD was predicted to increase Cmax 1.7-fold versus normal renal function. 959 | FDA concentration-QTc analysis at 24 g (concentration 195.6 µg/mL) estimated placebo-adjusted ΔΔQTc of −3.1 ms (90% CI −5.4 to −0.9 ms). The reviewer’s analysis excluded a 10-ms QTc prolongation effect at 24 g. The sponsor model predicted −0.31 ms (90% CI −3.989 to 6.010) at 24 g. 953 | No clinically relevant prolongation | The assessment was limited rather than waived. Although the TQT data supported absence of QTc prolongation at clinical exposure, they could not exclude QTc prolongation in the high-clinical-exposure renal-impairment scenario because 24 g did not cover that exposure. Assay sensitivity also could not be conclusively established because moxifloxacin ECGs were collected only through 4 hours post-dose; FDA performed QT-bias and sensitivity analyses, which confirmed the primary result. 951 |
| Rezzayo (rezafungin acetate) | 217417, 2023-03-22 169 | The supratherapeutic 1,400-mg dose was approximately 2.5 times the Cmax of the proposed 400-mg loading dose. The approved label characterizes the evaluated dose as 3.5 times the maximum approved recommended loading dose. 737 | For both rezafungin doses, the estimated mean placebo-adjusted ΔΔQTcF at geometric-mean plasma concentrations had confidence-interval upper bounds below 10 ms. The review also states that the thorough-QT study was negative. 737 | No clinically relevant prolongation | |
| Xacduro (Copackaged) (durlobactam sodium; durlobactam sodium; sulbactam sodium) | 216974, 2023-05-23 181 | The 4-g IV supratherapeutic dose was 4 times the maximum recommended single dose. It produced Cmax 96.2 µg/mL, 1.4-fold above the predicted high clinical Cmax of 70 µg/mL in severe renal impairment (and 3.4-fold above the cited clinical-dose Cmax). 718 | Primary by-time result: maximum mean placebo-corrected change in QTcF was 1.8 ms at 6 hours (90% CI, -1.0 to 4.5 ms), excluding a 10-ms effect. Supportive concentration-QTc analysis predicted ΔΔQTcF of 0.43 ms (90% CI, -1.38 to 2.23) at geometric-mean Cmax 106 µg/mL and excluded an effect >10 ms up to approximately 190 µg/mL. 721 | No clinically relevant prolongation | Not applicable: a dedicated thorough-QT study was performed. The review states that integrated nonclinical risk assessment was not conducted because the QT assessment pathway was a thorough-QT study. 718 |
| Inpefa (sotagliflozin) | 216203, 2023-05-26 253 | The study included 800 mg and 2,000 mg single doses; 2,000 mg was 5 times the maximum recommended dose of 400 mg once daily. 967 | Maximum mean placebo-adjusted, baseline-corrected QTc (ΔΔQTc) was 1.9 ms at 800 mg and 1.3 ms at 2,000 mg; associated upper confidence bounds were 3.7 ms and 2.4 ms, respectively. Thus, at 5 times the maximum recommended dose, sotagliflozin did not prolong QTc to a clinically relevant extent. 967 | No clinically relevant prolongation | |
| Zurzuvae (zuranolone) | 217369, 2023-08-04 173 | The regimen was zuranolone 50 mg once daily on Days 2–7 followed by 100 mg on Day 8 (i.e., 2 times the maximum recommended dose). The 100-mg supratherapeutic dose provided 1-fold coverage of the high clinical Cmax, defined as exposure with a strong CYP3A4 inhibitor (about a 1.25-fold increase in Cmax). Geometric-mean Cmax was 98.3 ng/mL after 50 mg on Day 7 and 134.0 ng/mL after 100 mg on Day 8. 1305 | At geometric-mean concentrations, FDA's QT-study summary reported ΔΔQTcF of 1.3 ms (90% CI −1.0 to 3.5) at 50 mg once daily on Day 7 and 2.2 ms (90% CI −0.5 to 4.8) at 100 mg. Thus, the upper 90% CI bounds were below 10 ms. The exposure-response analysis also predicted ΔΔQTcF of 0.52 ms (90% CI −4.10 to 5.13) at the Day-8 100-mg geometric-mean Cmax (132.8 ng/mL). 1301 | No clinically relevant prolongation | This was not waived: a dedicated TQT study was performed. FDA nevertheless noted a limitation: pharmacokinetics of metabolites, including a slowly eliminated metabolite with a reported terminal half-life of 127 hours, were not characterized in the TQT study. Seven days of treatment may have achieved only about 65% of that metabolite's steady-state exposure, so its potential QT effects were not adequately characterized; nonclinical QT testing of metabolites (for example, hERG) had also not been performed. FDA reviewed placebo-controlled patient-trial QTcF data, which showed no QT-prolongation or QT-related cardiac-adverse-event signal. 1301 |
| Sohonos (palovarotene) | 215559, 2023-08-16 259 | The supratherapeutic 50-mg single dose was 2.5 times the maximum recommended 20-mg flare-up dose and was stated to cover the worst-case CYP3A-inhibition exposure scenario. Geometric-mean Cmax at 50 mg was approximately 314 ng/mL; the QT model excluded a >10-ms effect over observed concentrations up to approximately 500 ng/mL. By comparison, predicted steady-state Cmax at the maximum proposed dose was 138–202 ng/mL. 1165 | At 50 mg, the concentration-QTcF model predicted placebo-corrected ΔΔQTcF of 0.95 ms (90% CI, -0.98 to 2.89 ms); the FDA analysis estimated 1.0 ms (90% CI, -0.5 to 2.4 ms) at 315.4 ng/mL. Thus, an effect exceeding 10 ms was excluded within observed concentrations up to approximately 500 ng/mL. No subject had QTcF >500 ms or ΔQTcF >60 ms. 1165 | No clinically relevant prolongation | |
| Aphexda (motixafortide acetate) | 217159, 2023-09-08 178 | The maximum recommended dose was 1.25 mg/kg SC. The supratherapeutic 2 mg/kg SC dose produced a geometric-mean Cmax of 2930 ng/mL, 1.7-fold (reported elsewhere as 1.74-fold) the high clinical Cmax of 1688.4 ng/mL in patients with multiple myeloma. 1175 | At the 1.7-fold-Cmax supratherapeutic exposure, mean placebo-corrected ΔΔQTcI/QTcI was 11 msec (90% CI 8 to 14 msec). At the therapeutic 1.25 mg/kg exposure, the concentration-QTc model predicted ΔΔQTcI 7.1 msec (90% upper confidence interval 9.2 msec), i.e., below 10 msec; the review states no significant QTc prolongation at the therapeutic dose. 1172 | QTc prolongation identified | |
| Ojjaara (momelotinib dihydrochloride) | 216873, 2023-09-15 185 | The therapeutic dose was 200 mg and the supratherapeutic dose was 800 mg. The 800-mg dose produced a mean Cmax 1.8-fold that of 200 mg. The review also notes that severe hepatic impairment increased momelotinib Cmax by 13% and food could increase Cmax by approximately 40%. 1067 | With QTcF, the largest upper bound of the two-sided 90% CI for the mean placebo-adjusted QTcF difference was below 10 ms for both 200 mg and 800 mg, the regulatory threshold of concern. The positive control established assay sensitivity: the largest lower bound of the two-sided 90% CI for moxifloxacin ΔΔQTcF was greater than 5 ms. 1068 | No clinically relevant prolongation | |
| Exxua (gepirone hydrochloride) | 021164, 2023-09-22 263 | The maximum tested regimen was gepirone IR 100 mg once daily with food. Day-7 geometric-mean Cmax was 55.3 ng/mL, versus 27.0 ng/mL for ER 80 mg once daily with food (about 2-fold clinical exposure) and 51.4 ng/mL in the then-described severe-renal-impairment high-exposure scenario (1.1-fold). Under the subsequently revised dosing context, Day 1 provided 1.5-fold clinical and 1.1-fold high-clinical exposure; Day 7 provided 2.0-fold clinical and 1.6-fold high-clinical exposure. 1249 | QTcF was prolonged. FDA’s by-time analysis found a largest mean placebo- and baseline-corrected QTcF increase of 17.4 ms (90% CI, 13.2–21.6) at 5 hours on Day 1 and 15.1 ms (90% CI, 11.1–19.0) at 3 hours on Day 7. The related approval review describes maximum observed mean effects of 18.4 ms (upper 90% CI 22.7 ms) on Day 1 and 16.1 ms (upper 90% CI 20.7 ms) on Day 7. Thus, the upper confidence bounds exceeded 10 ms. No participant had QTcF >480 ms or ΔQTcF >60 ms in the TQT study. 1250 | QTc prolongation identified | The standard assessment was not waived: FDA had required a TQT study before approval because the prior QT assessment was deficient and higher exposures had not been adequately assessed. However, FDA considered the submitted TQT study uncertain/limited: only one gepirone dose level was studied; Day 1 and Day 7 showed discrepant concentration-QTc relationships; food administration differed between days; metabolite contributions were unclear; and hERG data were unavailable. Accordingly, FDA did not accept C-QTc model extrapolation and imposed a postmarketing requirement for a new multiple-dose ER TQT study with therapeutic and supratherapeutic doses, placebo/positive control, and by-time analysis. 1252 |
| Velsipity (etrasimod arginine) | 216956, 2023-10-12 183 | The studied supratherapeutic dose was 4 mg once daily on Day 14—2 times the maximum recommended 2-mg dose. The documents do not provide a numeric Cmax or AUC exposure multiple for the TQT assessment. 1269 | Etrasimod was not associated with a significant QTc-prolonging effect at 4 mg on Day 14. No numerical mean QTc effect or 90% confidence-interval upper bound is provided in the retrieved rows. 1258 | No clinically relevant prolongation | |
| Zilbrysq (zilucoplan sodium) | 216834, 2023-10-17 186 | The supratherapeutic dose was 0.6 mg/kg, twice the recommended 0.3 mg/kg dose (2× maximum recommended dose), administered once daily for 7 days. This was the highest dose evaluated in humans and covered anticipated high clinical exposure. 1150 | Mean QTcF increase was 3.2 ms, with an upper bound of the 90% confidence interval of 5.3 ms. Exposure-response analysis did not suggest a significant QTc-prolonging effect; the by-timepoint analysis excluded the 10-ms threshold, and categorical analysis identified no outliers. 1150 | No clinically relevant prolongation | |
| Fabhalta (iptacopan hydrochloride) | 218276, 2023-12-05 147 | The 1,200-mg single dose provided greater than 4-fold the peak concentration at the maximum recommended human dose (MRHD; 200 mg twice daily). 1368 | The study showed no effect on cardiac repolarization or the QT interval. The provided documents do not report a numerical mean QTc change or confidence-interval upper bound. 1368 | No clinically relevant prolongation | |
| Zelsuvmi (berdazimer sodium) | 217424, 2024-01-05 168 | The study used SB204 12% applied as a single dose to approximately 17% body-surface area. This was approximately 33-fold the expected average SB206 10.3% gel application area for the molluscum contagiosum indication. 1099 | The supratherapeutic dose did not significantly increase QTcF; the cardiac-safety review concluded the data did not suggest a significant QTc-prolonging effect. No numerical mean QTc effect or 90% confidence-interval upper bound was provided in the retrieved rows. 1097 | No clinically relevant prolongation | For the marketed SB206 molluscum-contagiosum program, additional QTc evaluation was considered unnecessary in light of the prior SB204 thorough-QTc study and lack of quantifiable clinical exposure with SB206 12%; the retrieved excerpt presents this as the sponsor's question, but does not include FDA's response. In the maximal-use study, no subject had quantifiable plasma hMAP3 on Day 1 and two subjects had quantifiable concentrations on Day 15. 1098 |
| Rezdiffra (resmetirom) | 217785, 2024-03-14 158 | Resmetirom 200 mg once daily, stated to be 2 times the maximum recommended dose. 1374 | Resmetirom did not prolong the QTcF interval at 200 mg once daily. The provided documents do not report a numerical mean QTc effect or confidence-interval upper bound. 1374 | No clinically relevant prolongation | |
| Tryvio (aprocitentan) | 217686, 2024-03-19 162 | The supratherapeutic regimen was 100 mg once daily for 10 days—8 times the recommended 12.5-mg dose—and provided approximately 3-fold high clinical exposure. Maximum geometric-mean Cmax was 16.8 µg/mL at 100 mg on Day 10; the stated worst-case high clinical Cmax was 11.5 µg/mL (elderly female with high-fat meal). 1277 | The exposure-response analysis showed concentration-dependent QTc prolongation. At 100 mg once daily on Day 10, the placebo-corrected ΔΔQTcF was 8.8 ms, with a 90% CI of 7.0 to 10.7 ms; the upper bound therefore exceeded 10 ms. At 25 mg once daily on Day 10, ΔΔQTcF was 4.3 ms (90% CI 3.7 to 4.8 ms). No subject had QTcF >480 ms or a >60-ms increase from baseline. 1270 | QTc prolongation identified | |
| Duvyzat (givinostat hydrochloride) | 217865, 2024-03-21 157 | The 300-mg TQT dose (3–6 mg/kg) produced givinostat Cmax 409.65 ng/mL, 6.6-fold the parent-drug steady-state Cmax in DMD patients at therapeutic dosing (61.7 ng/mL). The approved label describes the analyzed 265.8-mg dose as approximately 5 times the recommended 53.2-mg dose for DMD patients weighing ≥60 kg. Metabolite coverage and the high clinical-exposure scenario were not established. 1327 | At 5 hours, placebo-corrected change from baseline QTcF was 5.5 ms (90% CI, 2.0–9.0) with 100 mg, excluding the 10-ms threshold; with 300 mg it was 13.6 ms (90% CI, 10.1–17.1), exceeding 10 ms. The approved label reports a largest mean QTc increase of 13.6 ms, with upper confidence interval 17.1 ms, at 5 hours after 265.8 mg in healthy subjects. 1321 | QTc prolongation identified | The assessment was not waived, but its exposure characterization was limited: the sponsor had not determined the high clinical exposure, anticipated in hepatic impairment, because organ-impairment studies had not been performed. Metabolite concentrations were not measured in DMD patients, so metabolite coverage by the TQT dose was unknown. The planned parent concentration-QTc model was considered unreliable/misspecified because of hysteresis and a nonlinear concentration-QTc relationship; metabolites were not incorporated into the model despite the QTc peak at approximately 5 hours being consistent with metabolite Tmax. 1320 |
| Vafseo (vadadustat) | 215192, 2024-03-27 198 | The study tested 600 mg and 1200 mg single doses; 1200 mg was supratherapeutic (4 times the approved 300-mg starting dose; 2 times the 600-mg maximum recommended daily dose) and was considered to cover the worst-case/high clinical exposure. Its observed Cmax was about 89 µg/mL versus about 72.5 µg/mL at steady state with 600 mg once daily in dialysis-dependent patients. 1039 | FDA by-time analysis: the largest reported ΔΔQTcF was 3.3 ms at 8 hours after 1200 mg (90% CI, 1.0 to 5.7 ms); thus the upper bound was below 10 ms. The concentration-QTc model predicted ΔΔQTcF of 2.4 ms (90% CI, 1.5 to 3.3 ms) at 89.1 µg/mL after 1200 mg. No QTcF value exceeded 480 ms and no ΔQTc exceeded 60 ms. 1035 | No clinically relevant prolongation | |
| Zevtera (ceftobiprole medocaril sodium) | 218275, 2024-04-03 148 | Single IV 500 mg and 1,000 mg were studied; 1,000 mg was 2 times the recommended dose. The label describes the evaluated range as 1 to 2 times the maximum recommended dose. 1571 | Ceftobiprole did not prolong the QT interval to any clinically relevant extent. The provided documents do not report a numerical mean QTc effect or confidence-interval upper bound. 1571 | No clinically relevant prolongation | |
| Xolremdi (mavorixafor) | 218709, 2024-04-26 142 | The only TQT dose was a supratherapeutic single 800-mg dose (versus the 400-mg once-daily therapeutic dose). It was selected after SAD doses predicted to yield 2- to 3-fold the proposed 400-mg exposure, and covered the predicted exposure at 400 mg in severe hepatic impairment or with strong CYP3A4 inhibitors. 1462 | At 800 mg, the by-time analysis showed a maximum LS mean ΔΔQTcF of 15.6 ms at 4 hours (90% CI, 11.3 to 19.9 ms). QTcF LS mean exceeded 10 ms from 1.5 to 4 hours. The applicant’s C-QTc model predicted 14.28 ms at the 800-mg geometric-mean Cmax (5837 ng/mL; 90% CI, 11.69 to 16.87), but FDA regarded that model as inadequate because of hysteresis. 1456 | QTc prolongation identified | The standard clinical assessment was not waived, but interpretation at the recommended 400-mg dose was limited: that dose was not studied in the TQT trial; a ~1.5-hour concentration-QTc delay of unknown source prevented reliable extrapolation/dose-response inference; and hepatic impairment was not directly evaluated. FDA concluded QTc prolongation is expected at 400 mg, but its magnitude is uncertain. 1461 |
| Iqirvo (elafibranor) | 218860, 2024-06-10 137 | Elafibranor 120 mg and 300 mg once daily for 14 days were evaluated. These doses were 1.5-fold and 3.75-fold, respectively, above the recommended 80-mg dose; 300 mg covered the high clinical-exposure scenario in hepatic impairment. 1552 | FDA by-time analysis found no significant QTcF prolongation: at 120 mg, the ΔΔQTcF estimate was −0.6 ms (90% CI −4.9 to 3.6) at 0.5 hours; at 300 mg, it was −4.4 ms (90% CI −8.3 to −0.5) at 6 hours. Thus, the reported upper 90% CI bounds were below 10 ms. 1549 | No clinically relevant prolongation | |
| Sofdra (sofpironium bromide) | 217347, 2024-06-18 174 | The supratherapeutic QT dose was 1,038 mg topical sofpironium bromide gel under occlusion (sixfold the maximum recommended dose of 174 mg). Its geometric-mean Cmax was 2.427 ng/mL versus 0.7647 ng/mL in the sponsor's high clinical-exposure scenario (with paroxetine), a 3.2-fold exposure multiple; the approved label describes this as 3 times the exposure associated with the maximum approved recommended dose. 1500 | By-time analysis excluded the 10-ms threshold at the supratherapeutic dose. Mean ΔΔQTcF ranged from -3.5 ms (supratherapeutic dose, 10.5 hours) to 3.3 ms (therapeutic dose, 1 hour); the largest upper 90% confidence bound was below 10 ms for both doses. At 1 hour, ΔΔQTcF was 3.5 ms (90% CI, 2.0 to 4.9) for 173 mg and 0.8 ms (90% CI, -0.6 to 2.2) for 1,038 mg under occlusion. Moxifloxacin showed a peak mean ΔΔQTcF of 14.5 ms (90% CI, 13.08 to 16.00), supporting assay sensitivity. 1493 | No clinically relevant prolongation | Not applicable: FDA required a thorough-QT study after not agreeing with the sponsor's initial proposal to use a substitute for a thorough-QT study. 1500 |
| Ohtuvayre (ensifentrine) | 217389, 2024-06-26 170 | The maximum recommended dose is 3 mg twice daily. The TQT study evaluated a 9-mg single inhaled dose (3× the recommended unit dose), which produced approximately 4.3-fold higher Cmax and AUC than 3 mg. FDA defined the high clinical-exposure scenario as Cmax 1,725 pg/mL in moderate hepatic impairment receiving 3 mg twice daily; the TQT exposure multiple was 1.4× this high clinical exposure. 1380 | No significant concentration–ΔΔQTcF relationship was found (slope 0.0012 ms per ng/mL; 90% CI −0.00012 to 0.00260). At the 9-mg geometric-mean Cmax (2,341.9 pg/mL), predicted ΔΔQTcF was 3.66 ms (90% CI 0.66–6.66); the upper 90% CI bound was below 10 ms at both doses and all timepoints. A ΔΔQTcF effect >10 ms could be excluded through 3,650 pg/mL. At the defined high clinical exposure (1,725 pg/mL), predicted ΔΔQTcF was 3.8 ms (90% CI 0.8–6.9). 1381 | No clinically relevant prolongation | |
| Leqselvi (deuruxolitinib phosphate) | 217900, 2024-07-25 155 | The supratherapeutic 48-mg dose was 6 times the proposed maximum therapeutic dose of 8 mg twice daily. At the geometric-mean Cmax for 48 mg, the concentration-QTc estimate had a 1-sided 95% upper bound of 2.0 ms; at the maximum evaluated Cmax (2080 ng/mL), estimated ΔQTcF was 0.8 ms (upper bound 3.4 ms). 1645 | Placebo-adjusted ΔΔQTcF values were ≤10 ms at every time point. The largest placebo-adjusted least-squares mean was 4.8 ms at 8 hours after 48 mg, with a 95% upper bound of 8.2 ms. All mean QTcF increases were <5 ms. 1645 | No clinically relevant prolongation | |
| Livdelzi (seladelpar lysine) | 217899, 2024-08-14 156 | The recommended dose is 10 mg once daily. The TQT study tested a single 200-mg dose (20 times the recommended dose), producing parent Cmax 5,705 ng/mL. This was approximately 17-fold the modeled high clinical parent exposure (357 ng/mL) for patients with Child-Pugh A hepatic impairment and portal hypertension; the M2-metabolite coverage was 8.8-fold. 1666 | At the modeled high clinical exposure (parent concentration 257.0 ng/mL), predicted ΔΔQTcF was -0.6 ms (90% CI, -3.4 to 2.3). At 200 mg (5,704.5 ng/mL), predicted ΔΔQTcF was -2.1 ms (90% CI, -5.1 to 1.0). By-time analysis at 200 mg found a maximum LS-mean ΔΔQTcF of 1.7 ms, with upper bounds of 6.2 and 6.3 ms; assay sensitivity was established with moxifloxacin. 1661 | No clinically relevant prolongation | |
| Miplyffa (arimoclomol citrate) | 214927, 2024-09-20 201 | Arimoclomol 124 mg and 372 mg three times daily (372 and 1,116 mg/day) were studied; 372 mg three times daily was 3 times the maximum recommended dosage. The 600-mg citrate-salt TID regimen (equivalent to 372-mg free-base TID) was expected to cover the high clinical-exposure scenario. 1546 | At 600 mg citrate salt (372 mg free base) TID, concentration 4,823.5 ng/mL, the FDA exposure-response estimate of placebo-corrected ΔΔQTcF was 2.9 ms (90% CI, 1.4 to 4.3 ms); thus, the upper bound was below 10 ms. No subjects had QTcF >450 ms or ΔQTcF >60 ms. 1531 | No clinically relevant prolongation | |
| Cobenfy (trospium chloride; xanomeline tartrate) | 216158, 2024-09-26 194 | The highest TQT dose was xanomeline/trospium 125/30 mg twice daily, the maximum recommended dose, and it reached steady-state clinical/high clinical exposure (1×): xanomeline 11,100 pg/mL and trospium 8,700 pg/mL. The high clinical exposure was considered the same as clinical exposure because hepatic impairment was proposed to be contraindicated. 1605 | At 125/30 mg twice daily and the high clinical exposures, predicted placebo-corrected change from baseline QTcI was -2.5 ms (90% CI -8.0 to 3.0 ms); thus, the upper bound was below 10 ms. The concentration-QTc relationship was not positive: the xanomeline slope was negative and not statistically significant. Assay sensitivity was demonstrated with moxifloxacin: predicted QT effect 12.17 ms (90% CI 8.57 to 15.78 ms), with lower bound >5 ms. 1605 | No clinically relevant prolongation | Not waived: FDA had previously rejected use of earlier studies as TQT substitutes because their ECG recordings did not support adequate concentration-QTc analysis and did not cover sufficiently high exposure multiples. A dedicated TQT study was therefore conducted. Assessment was limited by substantial drug-related heart-rate increases that confounded QTcF interpretation; QTcI was used to address this limitation. 1611 |
| Rapiblyk (landiolol hydrochloride) | 217202, 2024-11-22 176 | The thorough-QT study had no substantial QT-altering effect. The review concluded that the overall findings were consistent with a low risk of Torsades de Pointes. In supportive published clinical-trial ECG data, QTc changes versus baseline were -0.004 seconds and -0.003 seconds in two landiolol groups, versus +0.001 seconds in the placebo group; comparisons versus placebo were not significant (p=0.8529 and p=0.9933). 1700 | No clinically relevant prolongation | ||
| Crenessity (crinecerfont) | 218808, 2024-12-13 138 | The TQT study evaluated 300 mg and 800 mg single doses with food; 800 mg produced mean Cmax 24,230 ng/mL, approximately 3.3-fold the applicant’s high-clinical-exposure scenario (7,267 ng/mL, reflecting a 1.3-fold CYP3A4-inhibition increase). The maximum recommended regimen was 100 mg twice daily with food. 1490 | At 10 hours, ΔΔQTcF was −5.0 ms (90% CI −7.2 to 2.8) with 300 mg and −9.8 ms (90% CI −12.0 to −7.6) with 800 mg. The upper bounds of the 90% CIs were below 10 ms at all time points for both doses. Crinecerfont therefore showed dose-dependent QTc shortening rather than prolongation; the small shortening at high clinical exposure was about −5 ms. 1487 | No clinically relevant prolongation | A standard linear concentration-QTc assessment was not used as the primary FDA analysis because peak QTc shortening occurred about 3–4 hours after peak crinecerfont concentration, violating the no-delay assumption. By-time analysis was supported by the sample size and used as the primary analysis. Integrated nonclinical risk assessment was not performed; hERG alone was evaluated, not other cardiac ion channels. 1487 |
| Alyftrek (deutivacaftor; tezacaftor; vanzacaftor calcium) | 218730, 2024-12-20 141 | Vanzacaftor 60 mg once daily (Form A) was studied versus the recommended 20-mg once-daily vanzacaftor dose in the triple combination. The TQT-study mean Cmax was 4.92 µg/mL versus 0.812 µg/mL at the therapeutic regimen (about 6-fold); it also covered the simulated highest clinical exposure with strong CYP3A inhibition (3.89 µg/mL) by approximately 1.3-fold. The label describes this as approximately 6 times the maximum recommended vanzacaftor dose. Separate tezacaftor and ivacaftor studies evaluated up to 3 times their respective maximum recommended doses. 1924 | At 60 mg, the concentration-QTcF model predicted ΔΔQTcF of 0.17 ms (90% CI −2.52 to 2.86) at geometric-mean Cmax (4,718.25 ng/mL); a >10-ms QTcF effect was excluded across observed vanzacaftor concentrations up to approximately 9,110 ng/mL. By-time analysis likewise had 90% CI upper bounds below 10 ms at every time point at therapeutic and supratherapeutic doses. The positive control demonstrated assay sensitivity (predicted moxifloxacin effect 6.93 ms; 90% CI 5.47 to 8.39). 1914 | No clinically relevant prolongation | No standard assessment was waived for vanzacaftor: the sponsor initially proposed concentration-QTc analysis from Study VX17-121-001 as a TQT substitute, but subsequently conducted the dedicated TQT study because those prior data did not provide sufficient exposure coverage. For tezacaftor and deutivacaftor, additional characterization was not considered necessary because exposures were covered by already approved products; FDA also stated that deuterated products were not known to differ in direct ion-channel interaction from their non-deuterated counterparts. The integrated review further supported extrapolating ivacaftor QT findings to deutivacaftor based on unlikely conformational change from deuteration, high protein binding, and comparable in-vivo exposures. 1916 |
| Journavx (suzetrigine) | 219209, 2025-01-30 125 | The maximum recommended regimen is a 100-mg loading dose followed by 50 mg every 12 hours. The QT study's 200-mg once-daily regimen covered the severe-hepatic-impairment high-exposure scenario by 1.2-fold for suzetrigine and 0.9-fold for M6-548; FDA concluded there was no significant QTc prolongation up to 2-times exposure of the maximum recommended dose. 2079 | At geometric-mean suzetrigine concentrations of 1251.7 ng/mL (Day 6) and 1163.8 ng/mL (Day 10), predicted placebo-corrected ΔΔQTcF was −0.70 ms (90% CI −3.83 to 2.42) and 0.66 ms (90% CI −3.75 to 2.44), respectively. A QTc effect exceeding 10 ms was excluded over observed concentrations up to approximately 2.16 µg/mL for suzetrigine and 3.0 µg/mL for M6-SUZ. No subjects on 200 mg once daily had QTcF >500 ms or ΔQTcF >60 ms. 2086 | No clinically relevant prolongation | |
| Gomekli (mirdametinib) | 219379, 2025-02-11 121 | Single 6 mg and 14 mg doses produced approximately 2-fold and 6-fold therapeutic exposure, respectively. The highest QT-study dose, 14 mg in healthy adults, had mirdametinib Cmax 1160 ng/mL versus the stated high-clinical-exposure Cmax of 222.2 ng/mL (reported Cmax ratio 5.2); metabolite PD-0315209 coverage was 0.9-fold (111 versus 126.4 ng/mL). 2132 | No clinically significant ECG effects were observed with 6 mg or 14 mg; central-tendency and diagnostic-statement analyses were consistent with absence of a clinically significant effect at supratherapeutic exposures up to 6-fold therapeutic exposure. FDA agreed that mirdametinib had no effect on the QTc interval. The retrieved rows do not provide a numerical mean ΔΔQTcF or 90% CI upper bound. 2129 | No clinically relevant prolongation | Not waived: a dedicated TQT study was conducted. A limitation in exposure coverage was that the 14-mg QT assessment covered the parent drug at 5.2-fold the stated high clinical exposure but PD-0315209 at only 0.9-fold; the high-exposure scenario was tentative pending a hepatic-impairment study. The glucuronide metabolite M22 was not measured in the QT or other PK studies because the applicant cited FDA guidance that Phase 2 conjugation generally makes compounds more water soluble and pharmacologically inactive. 2132 |
| Blujepa (gepotidacin mesylate) | 218230, 2025-03-25 149 | The 1,000-mg IV Cmax was approximately 1.2-fold the steady-state Cmax with 1,500 mg oral BID (the maximum recommended uUTI regimen). The 1,800-mg IV Cmax was approximately 1.2-fold the Cmax after the second 3,000-mg oral dose given 12 hours after the first dose. Mean TQT Cmax values were 7.3 and 13.6 µg/mL for 1,000 and 1,800 mg IV, respectively. 1821 | Dose- and concentration-dependent QTc prolongation occurred: mean placebo-corrected change from baseline QTcF around Tmax was 12 msec with 1,000 mg IV and 22 msec with 1,800 mg IV. For the original uUTI regimen, concentration-QTc analysis predicted ΔΔQTcF of about 8 msec at therapeutic exposure and about 17 msec at the high-exposure scenario (severe hepatic impairment), but FDA identified uncertainty in these predictions. 1818 | QTc prolongation identified | Not waived: a dedicated TQT study was conducted. The assessment was limited for translating the IV findings to repeat oral dosing because M4 was not measured in the TQT study, the relative M4 exposure after IV versus repeat oral dosing was unknown, and the high clinical exposure scenario (16.9 µg/mL) exceeded the highest TQT concentration (13.6 µg/mL). 1818 |
| Vanrafia (atrasentan hydrochloride) | 219208, 2025-04-02 126 | The maximum recommended dose is 0.75 mg once daily. The 6 mg single dose had mean Cmax 22.4 ng/mL versus the high clinical-exposure scenario of 15.7 ng/mL (0.75 mg with an OATP1B1/1B3 inhibitor causing a 4.3-fold Cmax increase), providing 1.4-fold coverage (40% higher). 1949 | The primary by-time analysis excluded a 10-ms QTcF effect at the supratherapeutic dose. Largest reported placebo-adjusted, baseline-corrected QTcF effects were 2.8 ms (90% CI, 1.0 to 4.6) for 1.5 mg at 8 hours and 3.1 ms (90% CI, 1.5 to 4.7) for 6 mg at 4 hours. FDA concentration-QTcF model predictions were 0.9 ms (90% CI, 0.5 to 1.3) at 2.4 ng/mL and 1.6 ms (90% CI, 0.5 to 2.7) at 19.7 ng/mL, respectively. No subject had QTcF >450 ms or ΔQTcF >60 ms. 1942 | No clinically relevant prolongation | |
| Ekterly (sebetralstat) | 219301, 2025-07-03 123 | The TQT regimen was 3,000 mg (900 mg at hours 0 and 1, then 1,200 mg at hour 2). This was 2.5 times the maximum recommended dose and produced geometric-mean Cmax about 18,000 ng/mL, 2.7-fold above the estimated Cmax (6,640 ng/mL) after two 600-mg doses 3 hours apart. It covered the defined high-clinical-exposure scenario (severe hepatic impairment, estimated Cmax 17,227 ng/mL). 1908 | At 5 hours after the 3,000-mg regimen, the largest mean ΔΔQTcF was 10.4 ms, with 90% CI 5.6 to 15.3 ms (upper bound 15.3 ms). QTc increase was concentration dependent. Thus, the study did not exclude the 10-ms regulatory threshold. 1902 | QTc prolongation identified | A standard dedicated TQT study was not waived; however, the planned concentration-QTc primary analysis was limited because hysteresis would cause a model without hysteresis to underestimate the effect at Cmax. FDA therefore relied on by-time analysis for the key result. Despite observed QTc prolongation, reviewers did not propose a Warnings and Precautions section because peak mean prolongation was about 10 ms (upper 90% CI about 15 ms), no clinically important ICH E14-type adverse events occurred in phase 3, and treatment is not chronic. 1903 |
| Sephience (sepiapterin) | 219666, 2025-07-28 115 | The study evaluated single doses of 60 and 120 mg/kg; 120 mg/kg produced a geometric-mean sepiapterin Cmax of 2.0 ng/mL and was the highest dose studied. This exposure was 0.8-fold the therapeutic Cmax after the recommended 60 mg/kg once-daily regimen, so it did not cover therapeutic Cmax. FDA considered the study adequate because there was no concentration-QTc relationship, no nonclinical QTc signal, and no identified high clinical-exposure scenario. 1930 | At geometric-mean Cmax, modeled mean ΔΔQTcF was -1.4 ms (90% CI, -2.5 to -0.3) at 60 mg/kg (1.7 ng/mL) and -1.5 ms (90% CI, -2.8 to -0.3) at 120 mg/kg (2.0 ng/mL). In by-time analysis, the upper bound of the two-sided 90% CI remained below 10 ms at every time point for both doses. No significant QTcF outliers (>500 ms or >60 ms over baseline) occurred. 1931 | No clinically relevant prolongation | A standard assessment was initially proposed to be limited/waived based on endogenous status and BH4-focused data, but FDA required assessment of both sepiapterin and BH4 because sepiapterin exposure after dosing was approximately 6-fold endogenous levels. The eventual TQT study's maximum sepiapterin exposure was below therapeutic Cmax; FDA nonetheless accepted it based on absent concentration-QTc relationship, negative nonclinical findings, structural equivalence to endogenous sepiapterin, and no known clinical or nonclinical proarrhythmic signal. 1934 |
| Modeyso (dordaviprone hydrochloride) | 219876, 2025-08-06 109 | The 750-mg single dose was 1.2 times the 625-mg once-weekly maximum recommended dose. Its mean Cmax was 4,223 ng/mL for dordaviprone and 797 ng/mL for ONC207—1.1-fold the highest therapeutic/clinical Cmax (3,830 and 729 ng/mL, respectively). The study dose encompassed therapeutic Cmax and the anticipated high-exposure scenarios of 375 mg with a strong CYP3A4 inhibitor (parent Cmax 4,425 ng/mL) and 625 mg in severe renal impairment (ONC207 Cmax 845 ng/mL). 1890 | Dordaviprone and ONC207 caused concentration-dependent QTc prolongation. At 750 mg, predicted mean ΔΔQTcF was 11.6 ms (90% CI, 9.6–13.6) at parent Tmax and 11.1 ms (90% CI, 9.6–12.6) at metabolite Tmax. At the maximum recommended regimen, predicted mean QTc increase was 11 ms (90% CI, 10–13 ms). The maximum by-time LS mean ΔΔQTcF increase was 13.8 ms (90% CI, 11.15–16.48) at 5 hours postdose. 1873 | QTc prolongation identified | Not waived: a dedicated TQT study was conducted. Residual uncertainty was stated for coadministration with a CYP3A4 inducer because predicted ONC207 Cmax at 625 mg (1,200 ng/mL) exceeds the ONC207 Cmax at the TQT maximum tolerated dose (797 ng/mL), and for severe hepatic impairment because pharmacokinetics were not evaluated in that population. Patient-study ECG data were also considered insufficient to provide useful information. 1875 |
| Brinsupri (brensocatib) | 217673, 2025-08-12 164 | The thorough-QT study evaluated a 120-mg single dose, stated as 4.8 times the highest recommended dose, with Cmax 837 ng/mL. The resulting labeled exposure margin was approximately 2 times the steady-state peak concentration at the maximum recommended daily dose in adults and adolescents with NCFB. 1978 | Brensocatib did not prolong the QTcF interval at the doses and exposures evaluated, including 120 mg single dose (Cmax 837 ng/mL). The retrieved documents do not provide a numerical mean QTc effect or 90% confidence-interval upper bound. 1978 | No clinically relevant prolongation | |
| Wayrilz (rilzabrutinib) | 219685, 2025-08-29 114 | The recommended regimen is 400 mg twice daily (mean steady-state Cmax 150 ng/mL). The high clinical-exposure scenario with strong CYP3A4 inhibition was 750 ng/mL (5-fold the clinical exposure). The highest QT-assessment regimen, rilzabrutinib 400 mg plus ritonavir 100 mg twice daily, produced a mean Cmax of 589 ng/mL—approximately 0.8-fold the projected high clinical exposure. The final label describes this as exposures 4-fold the highest recommended dose. 2058 | Rilzabrutinib did not cause QTc prolongation >10 ms. Instead, it produced concentration-dependent QTcF shortening: after a single 400-mg dose, mean maximum QTcF decrease was −7 ms (90% CI, −9 to −5) at 2 hours; at exposures 4-fold the highest recommended dose, the decrease was −10 ms (90% CI, −12 to −8) at 2 hours. In the exposure-response analysis, the predicted upper bound of the 90% CI for ΔΔQTc was below 10 ms at Cmax. 2062 | No clinically relevant prolongation | A standard assessment was not waived: a dedicated TQT study was performed. Although the supratherapeutic TQT Cmax reached only 0.8-fold the projected high clinical-exposure scenario, FDA considered that difference not significant, and the integrated review concluded that 400 mg with ritonavir adequately covered worst-case clinical exposures. The mechanism of the observed QTc shortening was not elucidated; reviewers noted that sodium-channel blockade could not be ruled out. 2056 |
| Forzinity (elamipretide hydrochloride) | 215244, 2025-09-19 197 | The supratherapeutic regimen was elamipretide 80 mg SC every 3 hours for five doses. It was intended to cover concentrations in patients receiving the maximum clinical dose of 40 mg SC once daily. The final label describes the assessed exposure as 3 times the peak concentration of the maximum recommended FORZINITY dose. Geometric mean concentration was 4,053 ng/mL with the supratherapeutic regimen, versus 2,160 ng/mL for 60 mg SC once daily in FDA analysis. 1804 | The TQT study was negative. At 80 mg SC every 3 hours for five doses, mean placebo-corrected change from baseline QTcF was negative at every post-dose time point (−0.3 to −4.7 ms). FDA exposure-response analysis estimated ΔΔQTcF of −1.93 ms (90% CI, −5.00 to 1.13 ms) at geometric mean concentration 4,053 ng/mL; thus, the upper bound was below 10 ms. 1805 | No clinically relevant prolongation | |
| Jascayd (nerandomilast) | 218764, 2025-10-07 140 | The 48-mg QT-study dose produced Cmax 430 ng/mL, approximately 1.2-fold the high clinical-exposure scenario in Japanese subjects (predicted steady-state Cmax 367 ng/mL) and 2.1 times the maximal concentration provided by the highest recommended dose, 18 mg twice daily, without pirfenidone (202 ng/mL). 2263 | Maximum adjusted mean placebo-corrected QTcF changes were 3.0 ms for 30 mg (90% CI, 0.7 to 5.4) and 3.2 ms for 48 mg (90% CI, 1.2 to 5.2); both two-sided 90% CI upper bounds were well below 10 ms. The cardiac-safety review table also reports the 48-mg result at 8 hours as 2.1 ms (90% CI, -0.9 to 5.1). 2262 | No clinically relevant prolongation | |
| Redemplo (plozasiran sodium) | 219947, 2025-11-18 106 | The therapeutic regimen was 25 mg every 3 months (mean steady-state Cmax 70.2 ng/mL). The TQT study used 100 mg SC (Cmax 344.1 ng/mL), providing a 4.9-fold Cmax/exposure multiple versus the clinical exposure; the label describes this as 4 times the recommended dose. 2255 | At 100 mg SC (344.1 ng/mL), the model-predicted placebo-corrected change from baseline QTcF was 0.3 ms, with a two-sided 90% CI of -1.1 to 1.7 ms. At the 25-mg clinical regimen exposure (70.2 ng/mL), ΔΔQTcF was -1.1 ms (90% CI -2.1 to 0.0). By-time analysis found ΔΔQTcF from -1.4 to 1.0 ms and an upper bound of the two-sided 90% CI below 5 ms at every post-dose time point. 2256 | No clinically relevant prolongation | Not waived: FDA initially agreed that Phase 3 time-matched ECG/PK data could be used if supplemented by a nonclinical risk assessment, but the applicant subsequently conducted a dedicated TQT study. No high clinical exposure scenario was identified. Supporting nonclinical findings included 1% hERG-current reduction at 6.2 µM (reported as 8,584-fold the high clinical exposure scenario) and no QTc changes in monkeys at an estimated free-Cmax multiple of about 1,274-fold; however, the review states that an integrated nonclinical risk assessment was not performed. 2253 |
| Nuzolvence (zoliflodacin) | 219491, 2025-12-12 118 | The highest formal TQT dose was 4 g fasted (geometric-mean Cmax 19.2–19.4 µg/mL), only 0.58-fold of the predicted high clinical Cmax of 32.9 µg/mL for a 3-g fed dose. The fed food-effect study evaluated up to 4 g and covered the Cmax of the worst-case clinical scenario; its maximum observed Cmax was 53.1 µg/mL. For the worst-case simulated scenario (female patients weighing ≥35 to <50 kg inadvertently taking 3 g fed), model-predicted QTc effects were evaluated at geometric-mean and 95th-percentile Cmax. 2411 | In the TQT study, the highest least-squares mean ΔΔQTcF was 1.42 ms (upper confidence limit 3.044 ms) after 2 g and 3.04 ms (upper confidence limit 4.674 ms) after 4 g; CI upper bounds were <10 ms at the geometric-mean concentrations. The C-QTc relationship was positive/linear. At the worst-case clinical exposure, predicted mean ΔΔQTc was 7.8 ms (upper 90% CI 10.6 ms) at geometric-mean Cmax and 11.2 ms (upper 90% CI 15.1 ms) at the 95th-percentile Cmax. No participant had QTcF >480 ms or ΔQTcF >60 ms after 2 or 4 g fasted; no clinically significant QTc prolongation was observed with 4 g fed in the food-effect study. 2407 | No clinically relevant prolongation | Not waived. The standard TQT assessment was limited for direct clinical-exposure coverage because the TQT was fasted whereas food increases Cmax about 1.5-fold; thus, the 4-g fasted TQT Cmax did not cover the relevant 3-g fed clinical Cmax. FDA considered extrapolation of the linear C-QTc model reasonable because the likely mechanism was hERG-mediated, but noted uncertainty because few observed C-QTc data were available above 30 µg/mL and rejected use of a specific 42.1-µg/mL safety threshold. The supportive food-effect ECG study lacked placebo and positive controls. 2409 |
| Myqorzo (aficamten) | 219083, 2025-12-19 130 | A single 50-mg dose was studied, producing exposure similar to 20 mg once daily at steady state (the high clinical dose/exposure described in the label). 2390 | The upper limit of the predicted placebo-corrected change from baseline in QTcF (ΔΔQTcF) 90% CI was <10 msec; the FDA interdisciplinary cardiac-safety review concluded that a single 50-mg dose did not cause a clinically meaningful QTc change. 2389 | No clinically relevant prolongation | |
| Lifyorli (Copackaged) (relacorilant) | 220641, 2026-03-25 96 | The assessment covered 3.8 times the mean maximal relacorilant concentration at the recommended dosage. 2275 | Clinically significant QTc interval prolongation was not observed at 3.8-fold the mean maximal concentration of the recommended dosage. No numerical mean QTc effect or confidence-interval bound was provided in the retrieved rows. 2275 | No clinically relevant prolongation | |
| Idvynso (doravirine; islatravir) | 216964, 2026-04-20 182 | The high dose was islatravir 240 mg (960 times the 0.25-mg maximum recommended daily dose). Its geometric-mean Cmax was 3.8 µM (1,194 ng/mL), approximately 855-fold the anticipated therapeutic Cmax; the QT review summarizes coverage as >1,000-fold high clinical exposure. 2338 | At the 240-mg dose (concentration 3.8 µM), the reviewer’s predicted placebo-corrected ΔΔQTcF was 3.6 ms, with a 90% CI of 0.6 to 6.6 ms—i.e., the upper bound was below 10 ms. The applicant’s QTcP concentration-QTc analysis similarly predicted 0.03 ms (90% CI −2.89 to 2.96 ms) at 240 mg. Supportive by-time analyses had 90% CI upper bounds below 10 ms at all time points. 2334 | No clinically relevant prolongation | Not waived: a dedicated thorough-QT study was performed. Although the review notes prior concerns regarding the nested-crossover design and analysis, the actual 3-week washout was considered adequate, and FDA concluded that islatravir did not prolong QTcF in the thorough-QT study. 2337 |
| Baxfendy (baxdrostat) | 219878, 2026-05-15 108 | The TQT study tested 16 mg and 32 mg single doses. The maximum proposed/recommended therapeutic dose was 2 mg once daily; thus, 32 mg was 16-fold the maximum recommended dose. The FDA review also states that exposure-response findings did not suggest a mean QTcF increase of ≥10 ms at therapeutic 4 mg once daily or supratherapeutic 16- and 32-mg doses. 2398 | Baxdrostat did not prolong QTc in the TQT study. Exposure-response analysis suggested no small mean QTcF increase (defined as ≥10 ms) at 4 mg once daily or at 16- and 32-mg doses. A numerical mean effect or 90% confidence-interval upper bound was not provided in the retrieved rows. 2398 | No clinically relevant prolongation | |
| Zaynich (cefepime hydrochloride; zidebactam) | 220787, 2026-05-29 94 | The TQT regimen was cefepime 2 g plus zidebactam 4 g IV over 60 minutes. Zidebactam 4 g was 4 times the maximum recommended zidebactam dose and provided 3.5-fold the steady-state therapeutic-dose zidebactam Cmax; cefepime 2 g was the recommended therapeutic dose. FDA stated there was no high clinical-exposure scenario because renal impairment increases AUC but not meaningfully Cmax and dosing is adjusted for eGFR ≤60 mL/min. 2295 | At 1.0 hour, the largest by-time mean ΔΔQTcF was 3.5 ms, with a highest upper bound of the 90% CI of 6.2 ms (90% CI 0.9 to 6.2 ms), below 10 ms. No subject had QTcF >500 ms or a >60-ms increase from baseline. Exposure-response analysis also found no clinically relevant effect; the predicted mean ΔΔQTcF at therapeutic-dose geometric mean Cmax was 3.84 ms (90% CI 1.69 to 5.999 ms). 2295 | No clinically relevant prolongation | Not waived: a dedicated TQT study was performed. The supratherapeutic coverage was limited for cefepime because the highest cefepime dose studied was the recommended therapeutic dose; FDA concluded no high clinical-exposure scenario existed for either component, based on the renal-impairment/Cmax and renal-dose-adjustment considerations. 2295 |
| Cypsedo (cipepofol) | 220482, 2026-05-29 98 | The highest QT-assessment dose was 0.4 mg/kg IV over 30 seconds—the recommended therapeutic regimen's initial dose—and covered the defined high clinical exposure. Mean Cmax was 2,790 ng/mL for cipepofol and 520 ng/mL for M4, for a Cmax ratio of 1.0 versus high clinical exposure (i.e., no supratherapeutic exposure margin). 2323 | The primary by-time analysis found LS mean ΔΔQTcI from -1.7 to 4.1 ms; the upper bound of the two-sided 90% CI was <10 ms at every post-dose time point. FDA's summary table reported the largest listed QTcF effect as 7.1 ms at 0.03 hours after 0.4 mg/kg, with 90% CI 3.6 to 10.6 ms. Supportive reviewer concentration-QTcI modeling predicted 6.0 ms (90% CI 4.2 to 7.9) at cipepofol Tmax and 2.0 ms (1.2 to 2.8) at M4 Tmax. 2308 | No clinically relevant prolongation | The standard assessment was not waived: FDA required a dedicated TQT study after concluding the earlier proposed multi-study ECG approach lacked sufficient information. Assessment was limited to therapeutic/high clinical exposure because no high-exposure scenario was identified and large supratherapeutic doses were difficult for an anesthetic. Bolus dosing caused rapid heart-rate increases that complicated QT interpretation; a constant infusion to achieve the bolus Cmax was considered to introduce safety risks, require mechanical ventilation, and raise ethical/interpretability concerns. Nonclinical hERG and dog data plus reviewer C-QTc analysis supported interpretation. 2330 |
| Utebzi (tebipenem pivoxil hydrobromide) | 215960, 2026-06-17 196 | The highest evaluated dose was 1200 mg as a single dose—2 times the maximum recommended UTEBZI dose. The review describes peak exposure as approximately 2-fold higher than the Cmax associated with the 600-mg TID clinical regimen; the observed 1200-mg Cmax was 14.6 µg/mL. 2554 | At 1200 mg (Cmax 14.6 µg/mL), the concentration-QTcF model estimated a mean placebo-corrected QTcF change of −2.2 ms, with 90% CI −4.3 to −0.0 ms. At 600 mg (11.1 µg/mL), the estimate was −1.5 ms (90% CI −3.1 to 0.2 ms). No subjects had QTcF >480 ms or ΔQTcF >30 ms. Moxifloxacin assay sensitivity was established (predicted effect 10.4 ms; 90% CI 8.4–12.4 ms). 2544 | No clinically relevant prolongation | A standard assessment was not waived: a dedicated TQT study was performed. Although the 1200-mg observed Cmax (14.6 µg/mL) was numerically below the cited maximum clinical steady-state Cmax (15.1 µg/mL), FDA considered extrapolation of the exposure-response relationship reasonable because the concentration-QTcF relationship was slightly negative and no high-clinical-exposure scenarios were expected to substantially increase tebipenem exposure. 2549 |
| Simtriyo (centanafadine hydrochloride) | 218145, 2026-07-24 153 | The highest regimen was 800 mg total daily dose (400 mg in the morning and 400 mg 5 hours later), providing approximately 2-fold coverage of the maximum recommended 280-mg once-daily ER dose. This was also considered adequate coverage above the highest exposure scenario from severe renal impairment (~40% increase in exposure). 2482 | No significant QTc-prolongation effect was detected in the dedicated thorough-QT assessment; FDA's cardiac-safety review concluded that the ECG/PK data supported exclusion of a QTc effect greater than 10 ms. 2483 | No clinically relevant prolongation |
C-QTc from phase 1 healthy-volunteer data (TQT substitute) (28)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Pyrukynd (mitapivat sulfate) | 216196, 2022-02-17 209 | The highest evaluated dose was 300 mg fasting. It provided approximately 6-fold higher AUC and Cmax than 50 mg BID (the maximum recommended/therapeutic dose), and >2-fold coverage of the known high clinical-exposure scenario (1.7-fold Cmax increase with a strong CYP3A inhibitor). 627 | FDA concentration-QTcF analysis estimated placebo-corrected ΔΔQTcF of 3.3 ms at 7,455 ng/mL after 300 mg, with a 90% CI of 2.0 to 4.5 ms (upper bound <10 ms). At 100 mg and 2,324.2 ng/mL, the estimate was 1.7 ms (90% CI 1.2 to 2.2). 628 | No clinically relevant prolongation | A separate positive control was waived because the 300-mg fasted dose was expected to provide 6-fold therapeutic-exposure coverage and >2-fold coverage of the known high clinical-exposure scenario. Assay sensitivity was therefore not assessed. 627 |
| Camzyos (mavacamten) | 214998, 2022-04-28 221 | The maximum healthy-volunteer dose was 25 mg once daily, versus the recommended clinical range of 2.5–15 mg once daily. This covered the pivotal-study target concentration range (<700 ng/mL). At 700 ng/mL (upper target concentration), the model-predicted mean QTc effect was 4.6 ms (90% CI −0.2 to 9.4 ms). At 25 mg once daily, geometric-mean concentration was 1,194 ng/mL, with predicted ΔΔQTcF 8.8 ms (90% CI 2.7 to 14.8 ms). 440 | In repeat-dose healthy volunteers, QTc increased concentration-dependently: predicted ΔΔQTcF was 2.7 ms (90% CI −1.8 to 7.2) at 482.4 ng/mL, 7.4 ms (1.8 to 13.0) at 1,033.3 ng/mL, and 8.8 ms (2.7 to 14.8) at 1,194.0 ng/mL. The 90% CI upper bound at 700 ng/mL was below 10 ms, but FDA stated the study lacked sufficient exposure margin to waive a positive control or exclude a small mean effect at that exposure. In HCM studies, predicted effects were negative at clinical doses/exposures—for example, −8.4 ms (90% CI −11.4 to −5.4) in oHCM and −8.2 ms (−11.2 to −5.2) in nHCM. 448 | QTc prolongation identified | The thorough-QT study was waived because it was considered unlikely to add insight beyond the multiple-dose healthy-volunteer data, which already indicated QTc prolongation; ECG collection in subsequent trials was recommended for patient safety. Assessment in patients was limited because ECGs were collected with trough PK only, so effects around steady-state maximum exposure might not have been captured. Nonclinical findings were mixed: mavacamten did not directly interact with hERG at therapeutic exposure, but QTc prolongation occurred in dogs and the mechanism remained unknown. 442 |
| Amvuttra (vutrisiran sodium) | 215515, 2022-06-13 216 | The highest studied dose was 300 mg SC (12× the 25-mg recommended quarterly dose). Its Cmax was approximately 1,090 ng/mL in healthy subjects versus an expected steady-state therapeutic Cmax of approximately 115.9 ng/mL in patients, a ~9.4-fold exposure margin. The final label describes the assessment as 12× the recommended dosage. 512 | At 300 mg, the concentration-QTc model predicted ΔΔQTcF of 1.5 ms, with a two-sided 90% CI of −2.7 to 5.8 ms; thus, the upper bound was <10 ms. No subject had QTcF >500 ms or ΔQTcF >60 ms at any dose level. 508 | No clinically relevant prolongation | A dedicated thorough-QT study was not conducted. FDA considered Study ALN-TTRSC02-001 adequate as an alternative. Because dosing is once quarterly, no increase beyond therapeutic Cmax was expected; consequently, the 300-mg dose was considered to sufficiently cover high exposures. The assessment was additionally supported by available nonclinical data and categorical ECG analysis. 505 |
| Relyvrio (sodium phenylbutyrate; taurursodiol) | 216660, 2022-09-29 233 | The highest studied regimen was one therapeutic-dose sachet (3 g sodium phenylbutyrate plus 1 g taurursodiol), administered as a single dose under fasting and fed conditions. Thus, exposure coverage was only at the therapeutic dose, not a supratherapeutic multiple; the high-clinical-exposure scenario was not identified because effects of organ impairment and drug interactions on parent/metabolite exposure had not been characterized. 424 | FDA by-time analysis found no suggestion of large mean QTcF increases: the largest reported point estimate was 1.5 ms (90% CI, -7.0 to 8.0) under fed conditions; fasting result was -3.0 ms (90% CI, -7.0 to 8.0). The assessment excluded large mean increases >20 ms at the therapeutic dose. Sponsor concentration-QTc predictions at mean Cmax had upper confidence intervals of 0.56 ms for phenylbutyrate, -2.75 ms for PAA, and 1.60 ms for taurursodiol, although FDA did not conduct its own concentration-QTc analysis because of inadequate exposure metrics for multiple moieties and unknown high clinical exposure. 423 | Not adequately characterized | No dedicated thorough-QT study was performed. The ECG studies lacked a positive control and a large exposure margin, and there was no integrated nonclinical safety assessment conducted according to best practices. Therefore, FDA was reluctant to conclude absence of a QT effect; it accepted exclusion only of large (>20 ms) QTc effects for the ALS indication. A TQT study was recommended if the product were pursued for additional indications. 427 |
| Orserdu (elacestrant hydrochloride) | 217639, 2023-01-27 165 | RAD1901-004 evaluated up to 1,000 mg QD (2.5× the maximum recommended 400-mg salt dose/345-mg free-base dose) and achieved geometric-mean Cmax 543 ng/mL. This did not cover the worst-case high clinical exposure with strong CYP3A4 inhibition (>4-fold Cmax increase). The 400-mg QD patient study covered anticipated therapeutic exposure but not worst-case exposure. FDA model predictions were 0.91 ms (90% CI −4.73 to 6.55) at 119.0 ng/mL (400 mg QD) and 1.84 ms (90% CI −9.14 to 11.83) at 559.3 ng/mL (400 mg QD plus a strong CYP3A4 inhibitor). 913 | No large mean QTcF effect (>20 ms) was observed. FDA's Phase 1 C-QTc model estimated ΔΔQTcF of 0.91 ms (90% CI −4.73 to 6.55) at therapeutic exposure and 1.84 ms (90% CI −9.14 to 11.83) at the modeled strong-CYP3A4-inhibitor exposure. FDA also reported a largest by-time ΔΔQTcF of 5.5 ms at 200 mg in RAD1901-004. However, the available data could not exclude smaller QTc increases. 909 | Not adequately characterized | A standard positive-control/dedicated TQT assessment was not performed. FDA stated that the studies lacked both a positive control and the large exposure margin over clinical exposures needed to waive a positive control. The 1,000-mg Phase 1 dose did not cover the anticipated high-exposure scenario with strong CYP3A4 inhibition, and sparse PK/ECG data in RAD1901-308 prevented adequate assessment at individual peak concentrations. Thus, FDA agreed that a mean increase >20 ms was not supported, but did not consider smaller QTc increases excludable. 908 |
| Zavzpret (zavegepant hydrochloride) | 216386, 2023-03-09 252 | The highest evaluated intranasal dose was 40 mg (2 × 20-mg sprays), versus the recommended 10-mg dose. It provided approximately a 4-fold margin over maximum therapeutic exposure (10-mg Cmax approximately 13.4 ng/mL) and approximately a 2-fold margin over the described worst-case exposure scenario. In the MAD study, maximum Cmax was approximately 48.2 ng/mL, approximately 1.7-fold the then-described high clinical exposure of 29 ng/mL. 672 | FDA exposure-response analysis at 40 mg once daily, concentration 47.7 ng/mL, estimated ΔΔQTcF was −1.7 ms (90% CI −4.2 to 0.9 ms). By-time analysis had upper 90% CI below 10 ms for all dose groups except the 5-mg Day-14 MAD cohort. The 5-mg Day-14 elevation was unexplained, was not seen on Day 1 or at higher doses, and analyses including or excluding that cohort yielded consistent overall conclusions. No participant had observed QTcF >480 ms or a change from baseline >60 ms. 671 | No clinically relevant prolongation | A positive control was waived because the 40-mg dose covered approximately two times the worst-case exposure scenario (moderate hepatic impairment and concomitant OATP1B3/NTCP inhibitors). The assessment was limited by lack of assay sensitivity/positive control; supportive nonclinical evidence showed a large hERG safety margin (>1,800-fold) and no QTc prolongation in monkeys at exposures exceeding high clinical exposure. The hERG assay had deviations from best practices (room temperature, no concentration verification, and no positive control), but reviewers considered these limitations not material to the large safety margin. 672 |
| Joenja (leniolisib phosphate) | 217759, 2023-03-24 160 | Therapeutic dosing was 70 mg twice daily (mean steady-state Cmax 3,790 ng/mL). The high-clinical-exposure scenario with a strong CYP3A4 inhibitor was 4,738 ng/mL (1.25-fold). The highest QT-assessment dose, 400 mg single dose, produced Cmax 14,300 ng/mL—3-fold the high clinical exposure. 790 | Exposure-response analysis did not suggest significant QTc prolongation. Predicted placebo-corrected QTcF effects were 0.0 ms (90% CI −1.4 to 1.4) at 70 mg twice daily, −0.1 ms (−1.6 to 1.4) at high clinical exposure, and −1.1 ms (−4.1 to 1.9) at 400 mg single dose (3-fold high-clinical exposure). No participant had QTcF >500 ms or ΔQTcF >60 ms. 790 | No clinically relevant prolongation | A dedicated TQT study was not required because FDA agreed that the proposed Phase 1 concentration-QTc study design and analysis could serve as an alternative under ICH E14 Q&A 5.1. A stated limitation was that digital ECGs were unavailable; ECGs were read fully automatically, and FDA had noted that absence of high-quality digital 12-lead ECG waveforms increases uncertainty in QT characterization. 794 |
| Veozah (fezolinetant) | 216578, 2023-05-12 189 | The highest tested exposure was after a single 900-mg dose (geometric-mean Cmax 5,346 ng/mL). It covered more than 2-fold the projected worst-case Cmax of 2,250 ng/mL for the approved 45-mg once-daily regimen, and approximately 15-fold the projected therapeutic Cmax of 354 ng/mL. The earlier model-defined supratherapeutic concentration of 1.5 micrograms/mL was more than 6-fold the therapeutic concentration. 848 | Both parent-only and parent-plus-metabolite models had upper 90% confidence bounds below 10 ms at therapeutic and supratherapeutic concentrations. At therapeutic concentrations, upper bounds were 3.2665 ms (Day 1) and 3.0945 ms (Day 7); at supratherapeutic concentrations, 4.4130 ms (Day 1) and 3.9233 ms (Day 7). FDA also found no concentration-dependent QTc prolongation. 847 | No clinically relevant prolongation | A dedicated thorough-QT study was not conducted because the ECG quality, achieved pharmacokinetic exposures, and predefined concentration-QTcF analysis were considered adequate. The high-dose SAD exposure provided more than a 2-fold margin over the anticipated worst-case exposure, which supported waiver of a positive control and the dedicated thorough-QT study. 854 |
| Litfulo (ritlecitinib tosylate) | 215830, 2023-06-23 258 | The model evaluated concentrations through the highest exposure after an 800-mg single dose, 12.5-fold the mean Cmax at the proposed 50-mg once-daily dose. The label describes the assessment as 12 times the mean maximum exposure of 50 mg once daily in alopecia areata patients. 682 | Across the entire studied concentration range, all upper bounds of the 90% CI for predicted ΔΔQTcF were below 10 ms. The upper 90% CI was 1.98 ms at the mean Cmax of 50 mg once daily, 3.06 ms at a supratherapeutic concentration (twice the exposure of 200 mg once daily), and 4.13 ms at the highest concentration after 800 mg single dose. 682 | No clinically relevant prolongation | Rather than conduct a separate dedicated TQT study, the sponsor used Study B7981001 for concentration-QTc analysis; FDA documented that this study appeared adequate as an alternative to a TQT study. 685 |
| Xdemvy (lotilaner) | 217603, 2023-07-24 166 | The highest QT-assessment dose was 600 mg as a single oral dose (mean Cmax about 4,990 ng/mL), approximately 280-fold above the steady-state therapeutic ophthalmic Cmax (17.8 ng/mL); it also covered the stated worst-case oral ingestion scenario of a 75-mg bottle. 664 | FDA exposure-response predictions showed ΔΔQTcF of 3.1 ms (90% CI, -0.9 to 7.2 ms) at 100 mg—the high clinical-exposure/overdose scenario—and -0.8 ms (90% CI, -6.4 to 4.8 ms) at 600 mg. No significant QTcF-prolongation effect was detected. 663 | No clinically relevant prolongation | Routine safety ECGs in the ophthalmic Study TRS-012 did not adequately characterize ocular-administration QT risk. Therefore, the oral healthy-volunteer concentration-QT assessment was extended to the ophthalmic product as a TQT substitute. A positive control was considered unnecessary because the 600-mg oral exposure provided an approximately 280-fold therapeutic-exposure margin. 665 |
| Agamree (vamorolone) | 215239, 2023-10-26 260 | The highest QT-assessment regimen was 20 mg/kg oral tablets, with ECG-matched geometric-mean Cmax 2,101 ng/mL. This was 1.6-fold the sponsor's high clinical-exposure scenario (1,355 ng/mL, accounting for CYP3A4 inhibition) and corresponds to 1.6 times the approved recommended dose in labeling. The exposure margin was below 2-fold, so it was not sufficient to waive a positive control or exclude a 10-ms effect. 1051 | FDA exposure-response estimates were ΔΔQTcF −3.1 ms (90% CI −12.6 to 6.5) at the 6 mg/kg once-daily low-fat-meal clinical regimen (Cmax 1,255 ng/mL), and −4.5 ms (90% CI −14.8 to 5.8) at 20 mg/kg (Cmax 2,101 ng/mL). Thus, the assessment could exclude large mean QTc increases (≥20 ms), but not a 10-ms effect. The FDA review noted a concentration-dependent QTc-prolongation effect over the studied concentration range. 1052 | Not adequately characterized | A dedicated TQT study was not performed; FDA had agreed that the clinical studies could serve as an alternative to TQT assessment. The assessment was limited because the high clinical exposure for the marketed formulation was uncertain and the observed exposure margin was <2-fold; there was no positive control, so assay sensitivity could not be established. FDA therefore considered the study adequate only to exclude mean QTc effects ≥20 ms. ECGs were scanned paper tracings rather than high-quality digital 12-lead waveforms, increasing uncertainty and variance in QT measurement. An integrated nonclinical-clinical assessment was not used because the hERG assay and in-vivo QT evidence did not support it. 1046 |
| Exblifep (cefepime hydrochloride; enmetazobactam) | 216165, 2024-02-22 193 | The highest QT-study dose was enmetazobactam 4 g as a single 30-minute IV infusion. It provided approximately 12-fold coverage of the clinical exposure and 6.6-fold coverage of the high clinical exposure (defined as 0.5 g every 8 hours over 2 hours in end-stage renal disease patients receiving dialysis). The geometric-mean Cmax used for the highest-dose model prediction was 233.6 µg/mL; the high-clinical-exposure concentration was 35.6 µg/mL. 1353 | The concentration-QTc model predicted ΔΔQTcF of -6.15 ms, with upper 90% CI 0.756 ms, at the highest-dose geometric-mean Cmax (233.6 µg/mL). At the proposed therapeutic-dose high-exposure scenario, predicted ΔΔQTcF was -2.2 ms, with upper 90% CI 0.8 ms. Thus, the upper bounds were below 10 ms. No subjects had QTcF >450 ms with ΔQTcF >60 ms. 1353 | No clinically relevant prolongation | A standard dedicated TQT study was waived/substituted because AT-101 was judged adequate to characterize enmetazobactam's QTc effect, including adequate supratherapeutic exposure coverage. The assessment was limited to the enmetazobactam component: cefepime had not undergone a thorough-QTc assessment either at its 1996 original approval or in this application; however, QTc prolongation was not described in cefepime labeling. AT-301 could not materially support FDA's primary review because it had only screening plus one nonstandardized post-dose ECG and no collected PK samples. 1353 |
| Lumisight (pegulicianine acetate) | 214511, 2024-04-17 203 | The maximum QT-study dose was 4 mg/kg IV (versus the recommended 1 mg/kg), with Cmax 99.5 µg/mL. This was 2.7-fold the projected high clinical exposure (36.3 µg/mL), representing a possible two 1-mg/kg injections 6 hours apart. 1517 | At the projected high clinical exposure (36.3 µg/mL), predicted ΔΔQTcF was 0.3 ms (90% CI, −2.4 to 3.0 ms). At 4 mg/kg / 99.5 µg/mL, predicted ΔΔQTcF was 2.5 ms (90% CI, −1.2 to 6.1 ms); thus, the upper bound was below 10 ms. The exposure-response slope was insignificant, and no subject had QTcF >480 ms or a change from baseline >30 ms. 1517 | No clinically relevant prolongation | No dedicated thorough-QT study was performed because the FDA QT Interdisciplinary Review Team determined that the ECG/PK assessment from CLP00201 was adequate and could serve as a substitute for a thorough-QT study. The assessment was supported by categorical analysis and nonclinical data described as showing no QTc prolongation. 1513 |
| Orlynvah (probenecid; sulopenem etzadroxil) | 213972, 2024-10-25 204 | The highest studied regimen was sulopenem 2800 mg IV over 1 hour, with geometric-mean Cmax 109.7 µg/mL. This was described as at least 40-fold the peak sulopenem concentration after a single oral ORLYNVAH dose; the oral 500 mg sulopenem etzadroxil/500 mg probenecid tablet Cmax was approximately 1.6–1.9 µg/mL. 1415 | At the 2800-mg IV exposure (Cmax 109.7 µg/mL), predicted ΔΔQTcF was 0.07 ms, with 90% CI −4.20 to 4.34 ms (upper bound 4.34 ms). The QT Interdisciplinary Review Team concluded that sulopenem does not prolong QTc. 1418 | No clinically relevant prolongation | A dedicated thorough-QT study was not conducted because FDA determined in September 2017 that Phase 1 Study A7371007 data were adequate as its substitute. No thorough-QTc assessment was conducted for probenecid in its original 1951 approval or this application; however, QTc prolongation was not described as an adverse reaction in probenecid labeling. 1415 |
| Attruby (acoramidis hydrochloride) | 216540, 2024-11-22 190 | The labeled assessment was at approximately 1.2 times the steady-state Cmax at the recommended 712-mg twice-daily dose. In healthy volunteers, a single 1,780-mg dose produced average peak concentrations of 18,100±9,170 ng/mL, versus average patient steady-state Cmax of 15,641±10,639 ng/mL. The phase-1 QT assessment included doses up to 2,000 mg; parent-drug Cmax coverage was approximately 1-fold versus the high clinical exposure, but acoramidis acylglucuronide coverage was approximately 0.5-fold. 1409 | The mean QTc effect was less than 10 ms in healthy volunteers after the 1,780-mg single dose; the submitted phase-1 analysis stated that QTcF prolongation exceeding 10 ms was excluded up to approximately 27,500 ng/mL. 1409 | No clinically relevant prolongation | The TQT study was substituted with phase-1 C-QTc plus integrated nonclinical evidence because no high clinical exposure scenario had been identified. Assessment was limited because hepatic impairment had not been evaluated and the major acylglucuronide metabolite was only covered to approximately 0.5-fold of therapeutic Cmax in the phase-1 QT assessment; supportive patient ECG/PK data and negative parent-drug hERG/in-vivo findings were used to address this limitation. 1401 |
| Romvimza (vimseltinib) | 219304, 2025-02-14 122 | The labeled supratherapeutic regimen was vimseltinib 40 mg once daily for 5 days, equivalent to 3.3 times the maximum recommended weekly dose. The original review also states that the highest tested QT-assessment regimen (40 mg twice daily for 5 days) provided 1.8-fold the tentative high clinical exposure; the concentration-QTc analysis covered observed plasma concentrations up to 1,774 ng/mL and the applicant described exposures exceeding twice the mean maximum exposure at the recommended dosage. 2115 | At 40 mg once daily for 5 days, the largest mean QTc increase was 8.2 ms, with upper confidence bound 12.3 ms; the effect was concentration-dependent. The review further states that a ΔΔQTcF effect exceeding 10 ms could be excluded across observed concentrations up to 1,774 ng/mL. 2115 | QTc prolongation identified | The sponsor sought FDA agreement to preclude a dedicated TQT study and use the QTc assessment in Study DCC-3014-01-002 as its substitute. Assessment remained limited for moderate/severe hepatic impairment because its effect on vimseltinib exposure had not been characterized; since QTcF increased in a concentration-dependent manner, the QTc effect in those patients was unknown. 2105 |
| Anzupgo (delgocitinib) | 219155, 2025-07-23 128 | The highest QT-assessment dose was a single 12-mg oral dose (mean Cmax 96.4 ng/mL), versus 0.5 ng/mL at the highest therapeutic/clinical topical regimen (20 mg/g twice daily), providing a 193-fold Cmax exposure margin. No intrinsic or extrinsic factors were considered to have a clinically relevant effect on exposure. 2037 | The concentration-QTcF model predicted ΔΔQTcF of 1.3 ms (90% CI, −0.9 to 3.4) at the highest therapeutic/clinical regimen concentration (0.5 ng/mL), and 2.8 ms (90% CI, 0.1 to 5.5) at 12 mg oral (96.4 ng/mL). Thus, the upper bound remained below 10 ms at the supratherapeutic exposure. 2036 | No clinically relevant prolongation | A dedicated thorough QT study was not performed because the healthy-volunteer concentration-QTc assessment at 193-fold clinical exposure was accepted as a substitute for a TQT study under ICH E14 Q&A 5.1. The review also states that integrated nonclinical risk assessment was not performed. 2034 |
| Palsonify (paltusotine hydrochloride) | 219070, 2025-09-25 131 | The 240-mg single oral-solution dose produced Cmax 1341 ng/mL—4.6-fold the Cmax at 60 mg once daily and 2.3-fold the anticipated high clinical-exposure Cmax (580 ng/mL, reflecting a 2-fold increase with a CYP3A4/P-gp/BCRP inhibitor). 2068 | At 240 mg (Cmax 1341.28 ng/mL), modeled ΔΔQTcF was 6.0 ms (90% CI, 0.2 to 11.8 ms). The exposure-response analysis did not suggest small mean QTcF increases of ≥10 ms; FDA concluded no clinically significant QTc prolongation in Trial 14. 2067 | QTc prolongation identified | A full dedicated thorough-QT study was not performed because the supratherapeutic healthy-volunteer SAD study was accepted as a substitute under ICH E14 Q&A 5.1. This acceptance was conditional on the therapeutic dose not exceeding 60 mg/day with the SSD formulation. 2070 |
| Rhapsido (remibrutinib) | 218436, 2025-09-30 146 | The highest QT-assessment dose was 600 mg once daily (Cmax 532 ng/mL), versus the applicant’s high clinical-exposure scenario of 195 ng/mL (25 mg twice daily with a 3.3-fold CYP3A4-inhibition increase), a 2.68-fold Cmax multiple. The approved label instead describes approximately 9 times the mean steady-state peak concentration at the recommended dose. 2188 | A concentration-dependent QTc prolongation signal was observed (appearing hERG-mediated). At 600 mg once daily (Cmax 531.5 ng/mL), estimated ΔΔQTcF was 7.5 ms, with a 90% CI of 5.0 to 10.0 ms. The label conclusion was that clinically significant QTc prolongation was not observed at approximately 9-fold the mean steady-state peak concentration from the recommended dose. 2186 | QTc prolongation identified | A dedicated TQT study was waived because FDA had previously determined that the phase 1 studies appeared adequate to characterize QTc-prolongation potential under ICH E14 Q&A 5.1, and later agreed the risk was adequately characterized by CLOU064X2101 and CLOU064X1101 as a TQT substitute. 2187 |
| Nereus (tradipitant) | 220152, 2025-12-30 103 | The maximum recommended single dose is 170 mg fasted (Cmax 110.5–112 ng/mL); the specified high clinical exposure with strong CYP3A4 inhibition/nonfunctional CYP3A4 variants was 143 ng/mL (1.3-fold). The study included an 800-mg single fasted dose; however, the reviewer used the median of the highest concentration quantile (125.5 ng/mL) because the 800-mg result was inconclusive. Thus, the analysis covered the high-exposure scenario for a single 170-mg dose without food, but not fed exposure: food increases Cmax about 6.9–7.0-fold at 170 mg. 2151 | Predicted ΔΔQTcF was 0.6 ms (90% CI −1.8 to 2.9) at 170 mg fasted (110.5 ng/mL), and 2.5 ms (90% CI −2.9 to 7.9) at the 143-ng/mL high clinical exposure. At 800 mg (276.6 ng/mL), ΔΔQTcF was 6.0 ms (90% CI −4.8 to 16.7), which was inconclusive because its CI included both 0 and 10 ms. No dose-dependent QTc changes were observed in by-time analysis. 2151 | Not adequately characterized | The standard dedicated TQT study was not conducted; the healthy-volunteer ECG/PK study was accepted as a substitute only for fasted 170-mg use. Assessment was limited because the fed state produces substantially higher exposure (approximately 6.9–7.0-fold higher Cmax at 170 mg) outside the studied concentration range; the applicant agreed to a postmarketing-commitment TQT study in the fed state. Other newer studies had only predose/end-of-study ECGs and were not adequate for QTc assessment. 2160 |
| Icotyde (icotrokinra hydrochloride) | 220149, 2026-03-17 104 | The assessment covered 5 times the maximum recommended dose (maximum studied dose 1000 mg versus the 200-mg recommended dose). FDA stated that renal impairment did not significantly increase Cmax and therefore the PN-235-01 high dose covered the high clinical-exposure scenario. Earlier, the 1000-mg dose had a mean Cmax about 4- to 4.8-fold the therapeutic-dose mean Cmax (9.9 ng/mL versus 2.1–2.5 ng/mL). 2139 | The QTc assessment supported exclusion of a mean QTc increase of ≥10 ms; the concentration-QTc analysis showed no effect. No numerical mean QTc estimate or confidence-interval bound is provided in the retrieved rows. 2140 | No clinically relevant prolongation | A dedicated TQT-study substitute was initially uncertain because body weight and potentially renal function, a major elimination route, could affect pharmacokinetics; the renal-impairment study was then pending. After renal-impairment evaluation showed no significant Cmax increase, FDA agreed that the PN-235-01 high dose covered high clinical exposure. The rows do not provide a separate final waiver rationale for not conducting a dedicated TQT study. 2139 |
| Xocova (ensitrelvir) | 220442, 2026-05-29 274 | A 2000-mg single dose provided approximately 3.4-fold the exposure at the recommended dose (and Cmax approximately 3.4-fold higher than mean Day-5 Cmax at the recommended dose). 2507 | Across 20–2000 mg, the upper bounds of the 90% CIs for QTcF estimates were all below 10 ms. At 2000 mg (96.9 mcg/mL), placebo-adjusted QTcF was 2.8 ms (90% CI, -1.1 to 6.6 ms). At the high clinical-exposure scenario (42.8 mcg/mL), it was -0.3 ms (90% CI, -2.6 to 2.0 ms). 2506 | No clinically relevant prolongation | |
| Ambelvist (gadoquatrane) | 219627, 2026-06-12 116 | The highest QT-assessment dose was 0.2 mmol Gd/kg (5 times the recommended 0.04 mmol Gd/kg dose), with mean Cmax 1,785 µmol Gd/L. This was 3.6-fold the high-clinical-exposure Cmax of 492 µmol Gd/L (mild renal impairment scenario). 2515 | No clinically relevant QTc effect/prolongation was found in the concentration-QTc analysis. The retrieved documents do not provide a numerical mean ΔQTc or 90% confidence-interval upper bound. 2515 | No clinically relevant prolongation | A dedicated thorough-QT study was waived because the accepted Phase 1 concentration-QTc assessment did not show QTc prolongation. During development, FDA noted that the 0.2 mmol Gd/kg study exposure did not provide at least 2-fold coverage of observed Cmax in mild renal impairment at 0.1 mmol Gd/kg and therefore recommended supplementation with an integrated nonclinical QT assessment. 2518 |
| Lipfendra (enlicitide decanoate) | 220848, 2026-07-15 93 | The Cmax margin was 4-fold relative to the Cmax at the 20 mg once-daily maximum recommended dose. The clinical-pharmacology review states that the supratherapeutic regimen produced a Cmax four times the steady-state exposure for the proposed therapeutic dose. 2474 | No concentration-QTc relationship was observed, and clinically significant QTc interval prolongation was not observed at 4 times the clinical Cmax at the maximum recommended dose. A numerical mean QTc effect or confidence-interval bound was not provided in the retrieved rows. 2473 | No clinically relevant prolongation | A dedicated thorough QT study was waived/not conducted because FDA found the QTc effects sufficiently characterized by C-QTc analysis of time-matched PK/ECG data from Study PN012. 2473 |
| Orzeyful (oveporexton) | 220860, 2026-08-05 272 | QTc was assessed at exposures up to 11 times the mean steady-state Cmax at the maximum recommended dose. 2489 | There was no clinically relevant effect on QTc, defined as an effect of ≥10 ms, up to 11-fold the mean steady-state Cmax at the maximum recommended dose. 2489 | No clinically relevant prolongation | |
| Zenbexus (iberdomide hydrochloride) | 221075, 2026-08-13 270 | 2.6-times the mean maximum concentration produced by the recommended ZENBEXUS dosage. 2490 | At this exposure, a clinically relevant QT interval prolongation was not observed. 2490 | No clinically relevant prolongation | |
| Mimrylo (rusfertide acetate) | 220605, 2026-08-28 273 | 1.3 times the geometric mean rusfertide Cmax achieved with the maximum recommended weekly dose (108 mg). 2470 | Clinically significant QTc-interval prolongation was not observed at this exposure. 2470 | No clinically relevant prolongation | |
| Lisraya (brepocitinib tosylate) | 220106, 2026-08-27 277 | A supratherapeutic 200-mg dose was assessed, equal to 6.67 times the approved recommended dose; the maximum recommended dose is 30 mg once daily. 2562 | LISRAYA caused concentration-dependent QTc interval prolongation at 200 mg. At 30 mg once daily, clinically significant QTc interval prolongation is not expected. No mean QTc change or confidence interval was provided in the retrieved rows. 2562 | QTc prolongation identified |
C-QTc / ECG analysis in patient studies (alternative QT study) (29)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Scemblix (asciminib hydrochloride) | 215358, 2021-10-29 217 | The highest evaluated dose was 280 mg BID, covering the maximum therapeutic exposure. The concentration-QTc analysis evaluated 40 mg BID, 80 mg QD, 200 mg BID, and the high clinical-relevant exposure (HCRE; worst-case Cmax at 200 mg BID); estimated mean and upper 90% CI effects were below 10 ms at each. The FDA model estimated ΔQTcF of 3.5 ms (90% CI 2.5–4.6) at 40 mg BID (796 ng/mL) and 6.6 ms (90% CI 4.7–8.5) at 200–280 mg BID (5,329 ng/mL). 371 | The model showed a positive but shallow concentration-QTc slope. Estimated mean ΔQTcF and the upper bound of its 90% CI were <10 ms at therapeutic doses and HCRE; FDA concluded no large QTc effect (>20 ms). 373 | Not adequately characterized | A dedicated study was waived by FDA (26-Sep-2019). The nonclinical package was supportive: hERG IC50 was 11.4 μM (at least 30-fold free-Cmax margin at 200 mg BID), and no QTc prolongation occurred in dogs up to 18-fold the free Cmax at 200 mg BID. However, FDA's QT review stated that the patient study lacked placebo control and a high exposure margin sufficient to waive a separate positive control, so absence of any QT-prolongation effect could not be conclusively established. 369 |
| Vonjo (pacritinib citrate) | 208712, 2022-02-28 228 | The inadequate TQT study used a single 400-mg dose with Cmax approximately 3,774 ng/mL, which did not cover the predicted steady-state Cmax of approximately 9,400 ng/mL at the maximum recommended 200-mg twice-daily regimen. The patient ECG assessment was at 200 mg twice daily (the maximum recommended dose); 54 patients were evaluated. 494 | At 200 mg twice daily in PAC203, the maximum mean QTcF increase from baseline was 11 ms (90% CI, 5.3–16.7 ms). The increase was not dose- or concentration-dependent; 2/54 patients (3.7%) had a postbaseline QTcF increase >60 ms, and none had QTcF >500 ms. 477 | QTc prolongation identified | The standard TQT assessment was limited because PAC107's 400-mg single-dose Cmax (~3,774 ng/mL) did not cover steady-state therapeutic Cmax (~9,400 ng/mL) at 200 mg twice daily; thus it could not assess proarrhythmic risk at clinically relevant exposure. QTc effects were evaluated in PAC203 patients instead. 494 |
| Pluvicto (lutetium lu-177 vipivotide tetraxetan) | 215833, 2022-03-23 214 | Only the recommended/therapeutic regimen was studied: 7.4 GBq (200 mCi) every 6 weeks (up to 6 doses). PK was obtained only at the therapeutic dose, which was also the maximum tested dose; mean Cmax was 6.58 ng/mL and mean AUCinf was 52.3 ng·h/mL. Thus, no supratherapeutic exposure multiple was characterized. 615 | By-time analysis: the FDA estimate at 4 hours was ΔQTcF 2.0 ms (90% CI −1.4 to 5.4); across the substudy, LS mean ΔQTcF ranged from −5.2 to 2.1 ms. C-QTc modeling predicted 3.12 ms at observed geometric-mean Cmax 3.8 ng/mL (90% upper bound 5.5 ms), and 8.6–8.7 ms at estimated true mean Cmax 6.58 ng/mL (90% upper bound 13.6 ms). No large mean increase (>20 ms) was observed. 613 | Not adequately characterized | The assessment was limited because there was no positive control and no data at a sufficiently high multiple of clinically relevant exposure. There were only three common ECG/PK post-dose timepoints (1, 4, and 24 hours) in Cycle 1; the first paired ECG/PK assessment was one hour after infusion rather than during or at the end of infusion, so ECGs did not capture Tmax. Consequently, a small transient QTcF increase during or immediately after infusion could not be excluded. 614 |
| Terlivaz (terlipressin acetate) | 022231, 2022-09-14 238 | Patients received an initial 1 mg IV dose every 6 hours (4 mg/day) for up to 14 days; if serum creatinine had not decreased adequately after 3 days, dose could increase to 2 mg every 6 hours (8 mg/day). A quantitative exposure multiple relative to maximum recommended/high clinical exposure was not reported in the provided documents. 565 | The approved label reports no clinically meaningful QTcF change from baseline, with mean QTc increases <10 ms in 41 HRS-1 patients. However, FDA reviewers concluded that the limited patient-study ECG dataset could exclude only large effects (>30–60 ms), not accurately quantify QT effect; the QT-IRT could not reach a conclusion. QTcF outliers were numerically more frequent with terlipressin: >30-ms increase, 10/41 (24.4%) versus 5/48 (10.4%); new QTcF >500 ms, 2/41 (4.9%) versus 0/48. 576 | Not adequately characterized | A thorough-QT study was not performed by agreement with the Division. The assessment was limited because OT-0401 was not designed or powered as a TQT study; it used time-averaged analysis, two paper ECGs rather than triplicates, had approximately 50% missing ECGs on Days 7 and 14, had ECG timing/acquisition limitations, baseline ECG abnormalities and confounding from critically ill HRS patients, and sparse PK samples not collected at ECG times. The sponsor's predicted-concentration/QTc analysis was not considered interpretable. FDA noted that HRS patients were critically ill and intensively monitored; telemetry and caution with hypokalemia, hypomagnesemia, and concomitant QT-prolonging drugs were suggested. 568 |
| Rezlidhia (olutasidenib) | 215814, 2022-12-01 234 | The evaluated dose was the recommended 150 mg twice daily under fasting conditions (i.e., 1× the recommended dose). At steady state, the modeled geometric-mean Cmax was 3,014.5 ng/mL (with FDA analysis presented at Cmax,ss 3,136 ng/mL). The assessment did not evaluate higher clinical exposures, including the approximately 2.5-fold food-related increase in exposure; the model excluded a 20-ms mean effect only up to approximately 6,800 ng/mL. 777 | At 150 mg twice daily at steady state, predicted mean ΔQTcF was 6.1 ms, with upper 90% CI 9.3 ms (geometric-mean Cmax 3,014.5 ng/mL). FDA analysis at Cmax,ss 3,136 ng/mL estimated ΔQTcF 6.2 ms (90% CI 2.7–9.7 ms). Thus, the upper bound was <10 ms at recommended fasted exposure, although a concentration-dependent QTcF increase was observed. 775 | Not adequately characterized | A dedicated thorough-QT study was not used; FDA accepted the proposed alternative continuous-ECG/concentration-QT analysis in the patient substudy as reasonable to exclude a mean increase >20 ms at the planned therapeutic dose. However, its coverage was limited to 150 mg twice daily fasting. FDA noted that it did not cover increased exposure with food, while effects were concentration-dependent clinically and in vitro. Food increased Cmax by 191% after a single 150-mg dose in healthy subjects, so higher-exposure QTc impact could not be determined. 787 |
| Krazati (adagrasib) | 216340, 2022-12-12 229 | The model prediction was at the population geometric-mean steady-state Cmax after 600 mg twice daily—the recommended therapeutic dose (i.e., 1× the recommended dose/high clinical exposure). 744 | At 600 mg twice daily, predicted mean ΔQTcP was 18.8 ms (90% CI, 16.4–21.1 ms) at geometric-mean steady-state Cmax (2,240 ng/mL). The FDA cardiac-safety review concluded that mean QTc increases >20 ms could not be excluded by either by-time or concentration-QTc analyses; 6.6% of patients had QTc >500 ms. 744 | QTc prolongation identified | A thorough QT study was not conducted. The provided rows do not state a rationale for not conducting it. The concentration-QTc analysis was limited by absence of a placebo control. 751 |
| Vanflyta (quizartinib dihydrochloride) | 216993, 2023-07-20 180 | The highest evaluated continuation-therapy dose was 53 mg/day, stated to cover therapeutic exposure at the highest recommended continuation dose. At steady-state Cmax, predicted results were provided for 26.5 mg (Cmax,ss 293 ng/mL) and 53 mg (586 ng/mL); thus the assessment reached approximately 1× the highest recommended continuation-therapy exposure, rather than a supratherapeutic multiple. 1006 | Predicted concentration-dependent ΔQTcF at steady-state Cmax was 18.4 ms (90% CI 16.3–20.5) at 26.5 mg/day and 24.1 ms (90% CI 21.4–26.6) at 53 mg/day. Thus, the upper 90% CI exceeded 20 ms at both doses (20.5 and 26.6 ms, respectively). 1022 | QTc prolongation identified | A standard dedicated assessment was limited to patient-study C-QTc analysis. The previously requested Holter ECG study assessing QTc effects/safety during sudden heart-rate increases (such as exertion) was not conducted; FDA concluded that available QT-RR data reflected relatively rested, non-sudden heart-rate elevations and were inadequate, so safety with sudden heart-rate changes remained uncertain. FDA also noted selection and dose-adjustment limitations in the continuation-phase analysis: patients had already tolerated prior therapy, and dose escalation depended on QTcF change. 1004 |
| Fruzaqla (fruquintinib) | 217564, 2023-11-08 167 | The QT assessment used 5 mg once daily, 3 weeks on/1 week off—the recommended regimen. Fruquintinib Cmax was 299.6 ng/mL versus clinical Cmax 291 ng/mL (1.02-fold; approximately 1-fold coverage). M11 Cmax was 89.6 ng/mL versus the sponsor's high clinical M11 Cmax of 177.1 ng/mL (0.50-fold coverage). 1108 | At the observed M11 Cmax of 77 ng/mL, the model-predicted upper bound of the 90% CI for mean ΔΔQTcP was 0.0537 ms; at twice that Cmax (154 ng/mL), it was 4.00 ms—both below 10 ms. In the by-time analysis, upper 90% CI bounds for least-squares mean ΔΔQTcP and ΔΔQTcF on Cycle 1 Day 21 were below 10 ms at every nominal time. At Day 21, ΔΔQTcF was 1.6 ms (90% CI -1.4 to 4.7) at 299.6 ng/mL. 1101 | Not adequately characterized | A dedicated TQT study was not feasible because substantial accumulation of fruquintinib (~2- to 4-fold) and M11 (~20-fold) would require steady-state measurements or single doses above the tested 1–6 mg range; healthy volunteers had received only single doses up to 5 mg. Supratherapeutic dosing was also precluded by toxicity in patients, with doses above 6 mg unsupported by safety data. The assessment lacked a positive control and did not provide a large exposure margin: the highest dose did not cover high clinical M11 exposure and did not achieve at least 2-fold high-clinical exposure to waive a positive control. Therefore, FDA concluded it could exclude mean QTc prolongation ≥20 ms, but was reluctant to conclude there was no QTc effect. 1107 |
| Augtyro (repotrectinib) | 218213, 2023-11-15 150 | The assessed regimen was 160 mg QD for 14 days followed by 160 mg BID, with mean steady-state Cmax 713 ng/mL. This was 0.59-fold of the sponsor-defined high clinical exposure (1,212 ng/mL, representing a 1.7-fold Cmax increase with CYP3A4 inhibition). Although sponsor pooled C-QTc analyses included observed concentrations up to approximately 3,750 ng/mL (>5-fold the observed steady-state mean Cmax of 747 ng/mL at 160 mg QD), the IRT’s approval assessment notes the highest exposure in TRIDENT-1 was only 0.59-fold of high clinical exposure. 1125 | By-time analysis at 160 mg QD/BID showed maximum mean ΔQTcF 8.3 ms, with a 90% CI upper bound of 10.0 ms (Cycle 4 Day 1 predose). Sponsor C-QTc analyses had negative concentration-QTc slopes and predicted QTc increase <10 ms at the highest exposures reached; however, FDA did not rely on the linear C-QTc model. The IRT concluded that repotrectinib did not cause a large mean QTc increase (i.e., 20 ms) at therapeutic exposure, while declining to conclude there was no QTc effect because there was neither a positive control nor a large exposure margin. 1127 | QTc prolongation identified | A dedicated thorough-QT study was not used; the IRT classified the approach as an alternative QT study when a thorough QT study is not feasible. Assessment was limited because no positive control or large exposure margin was available, and the highest TRIDENT-1 exposure was 0.59-fold of the identified high clinical exposure. Linear C-QTc modeling was not relied upon because of large intercepts and negative slopes, possible plateau/nonlinearity or delayed QT effects, and limited within-subject exposure range. Healthy-volunteer studies were also of limited utility: only three achieved therapeutic concentrations and they used single, non-digital ECGs. 1124 |
| Truqap (capivasertib) | 218197, 2023-11-16 151 | The recommended regimen was 400 mg twice daily, 4 days on/3 days off. The highest QT-assessment dose was 800 mg on Day 1, with parent Cmax 2,108 ng/mL versus 2,275 ng/mL in the anticipated high-exposure scenario (400 mg twice daily plus a moderate CYP3A4 inhibitor): 0.93-fold coverage for parent. M2 exposure was 1.7-fold the anticipated high-exposure scenario (the QT-review summary alternatively reports 1.5-fold). 1223 | At the therapeutic-exposure Cmax of 1,750 ng/mL, predicted mean ΔQTcF was 6.1 ms (90% CI, 4.6–7.6). At the anticipated high clinical exposure with a moderate CYP3A4 inhibitor (2,275 ng/mL), predicted mean ΔQTcF was 8.1 ms (90% CI, 6.2–10.0). FDA concluded that QTcF was not prolonged by ≥20 ms at the therapeutic dose; QTc prolongation was concentration-dependent, but the 90% CI upper bound only reached 10 ms at the high-exposure scenario. 1218 | QTc prolongation identified | A standard dedicated thorough-QT study was not performed; FDA classified the assessment as an alternative QT study when a thorough-QT study is not feasible. The assessment was limited to first-dose data because only pre-dose PK–QT measurements were available after multiple dosing. Assay sensitivity and sponsor by-time analysis were not performed. 1218 |
| Ogsiveo (nirogacestat hydrobromide) | 217677, 2023-11-27 163 | Recommended dose: 150 mg twice daily. The high clinical-exposure scenario was Cmax 1,687.5 ng/mL (approximately 2.5-fold increase with strong CYP3A4 inhibition). The highest QT-assessment doses in A8641014 were 220 mg twice daily for 21 days (n=10) and 330 mg twice daily (up to 15 days); 220 mg twice daily produced geometric-mean Cmax 1,667.2 ng/mL, 0.99-fold of the high clinical Cmax—i.e., only about a 1-fold margin. At 150 mg, predicted ΔQTcF was assessed at 675 ng/mL and 1,687.5 ng/mL. 1082 | Model-predicted ΔQTcF was 0.8 ms (90% CI −1.8 to 3.3) at 675 ng/mL and 2.2 ms (90% CI −2.9 to 7.3) at 1,687.5 ng/mL; thus, the upper 90% CI remained below 10 ms at the high clinical-exposure scenario. Separately, FDA concluded that no concentration-QTc relationship was detected over the exposure range, but stated that the evidence did not support ruling out all QTc effect because of the design limitations. 1084 | Not adequately characterized | A standard dedicated TQT assessment was not performed; FDA used the alternative E14 Q&A 6.1 pathway because the available study had no placebo or positive control, no demonstrated assay sensitivity, and only a 1-fold exposure margin over the high clinical Cmax. FDA therefore concluded that nirogacestat did not cause large mean QTc increases (≥20 ms) at therapeutic exposure, but was reluctant to conclude that it has no QTc effect. Quantitative analysis was also limited by lack of digital ECGs for some studies, heterogeneous ECG acquisition/analysis, and inability to pool A8641014 and NIR-DT-103. 1075 |
| Voranigo (vorasidenib) | 218784, 2024-08-06 139 | The assessment was at vorasidenib 40 mg once daily, administered under semi-fasted conditions (1 hour before a meal). Exposure did not cover higher clinical exposure scenarios: a high-fat meal increases Cmax about 3-fold and strong CYP1A2 inhibition increases Cmax about 6-fold; coverage of food-related increases in the major metabolite AGI-69460 was also unclear. 1707 | At Cycle 1 Day 15, 2 hours post-dose, the placebo-adjusted change in QTcF (ΔΔQTcF) was 1.7 ms, with a 90% CI of -1.4 to 4.9 ms. FDA concluded that, under the studied semi-fasted 40-mg regimen, a mean QTcF increase >20 ms was unlikely. 1706 | Not adequately characterized | A dedicated thorough-QT study was not used; FDA considered AG881-C-004 an alternative QT study when a thorough-QT study was not feasible. The assessment was limited by absence of a positive control or a large exposure margin, so FDA was reluctant to conclude there was no QTc effect. The study also lacked PR and QRS interval collection, and its limited ECG/PK data could not support C-QTc modeling or evaluation of delayed QTc prolongation. 1707 |
| Lazcluze (lazertinib mesylate) | 219008, 2024-08-19 134 | The recommended dose was 240 mg once daily (steady-state geometric-mean Cmax 473 ng/mL). The high clinical exposure scenario was 1.2-fold with CYP3A4 inhibition (Cmax 568 ng/mL). The highest QT-assessment dose, 320 mg once daily, produced Cmax 592 ng/mL—1.04 times the high-clinical-exposure Cmax and 1.3 times the approved recommended dose. 1587 | Lazertinib showed concentration-dependent QTc prolongation, but the modeled effect was small: at 240 mg, predicted ΔQTcP was 3.54 ms (90% CI 1.24–5.83) and ΔQTcF was 3.52 ms (90% CI 1.11–5.93). At 320 mg, predicted ΔQTcP was 4.35 ms (90% CI 1.47–7.23) and ΔQTcF was 4.26 ms (90% CI 1.24–7.29). The upper bound of the 90% CI remained <10 ms; FDA concluded the maximum recommended regimen excluded a ≥20-ms mean QTcF increase. 1585 | Not adequately characterized | A dedicated thorough-QT study was not performed. FDA used the alternative-QT-study pathway because a thorough QT study was not feasible; the patient-study C-QTc dataset included high-dose exposure covering the high clinical exposure scenario. The assessment had no positive control, so assay sensitivity was not demonstrated. 1586 |
| Itovebi (inavolisib) | 219249, 2024-10-10 124 | The highest assessed regimen was inavolisib 9 mg with palbociclib and letrozole (geometric-mean Cmax 61.2 ng/mL), representing 0.8-fold of clinical exposure and 0.3-fold of the anticipated high clinical exposure. The approved 9-mg steady-state Cmax was 69 ng/mL; model prediction at 75.1 ng/mL (the stated geometric-mean therapeutic Cmax in the QT review) was also reported. Predicted 2- to 3-fold exposure in moderate/severe renal impairment was outside the GO39374 studied range. 1624 | At the geometric-mean steady-state Cmax of 75.1 ng/mL after inavolisib 9 mg once daily alone, predicted ΔQTcF was 4.2 ms (90% CI, 2.1-6.3 ms), with the upper bound below 10 ms. The applicant’s model showed a concentration-dependent slope but excluded a large mean increase (≥20 ms). FDA concluded that 9 mg daily was unlikely to cause a ≥20-ms mean QTc increase. 1626 | Not adequately characterized | A thorough QT study was not used; FDA categorized the program as an “alternative QT study when a thorough QT study is not feasible.” Key limitations were that the label-relevant inavolisib/palbociclib/fulvestrant combination in Arms E/F had limited ECG collections (primarily predose and 24 hours postdose), so these data were not included in the reviewer’s C-QTc analysis; in addition, predicted exposure in moderate/severe renal impairment (2-3-fold) was outside the assessed exposure range. The reviewer considered 0.8-fold geometric-mean therapeutic-Cmax coverage sufficient because therapeutic Cmax was within the range of individual Cmax values in the QT assessment. 1626 |
| Revuforj (revumenib citrate) | 218944, 2024-11-15 135 | The label describes evaluation over 113–339 mg twice daily (up to 1.2 times the highest adult approved recommended dosage), with and without strong CYP3A4 inhibitors. In the QT study, the highest observed revumenib Cmax was 3,552 ng/mL (226 mg twice daily with a strong CYP3A4 inhibitor), covering clinical and high clinical exposure for revumenib; the highest M1 Cmax was 510 ng/mL, covering clinical but not high clinical exposure for M1. 1688 | QTc prolongation was concentration-dependent. At mean steady-state Cmax at the highest approved recommended dosage without CYP3A4 inhibitors, predicted QTc increase was 27 ms (upper bound of the 90% CI, 30 ms); at 163 mg twice daily with strong CYP3A4 inhibitors, it was 19 ms (upper bound, 22 ms). FDA also reported a median ΔQTcF of 18–22 ms at the recommended Phase 2 dose. 1681 | QTc prolongation identified | A thorough QT study was not conducted because it was infeasible; the applicant submitted the cardiac safety report for Study SNDX-5613-0700 as an alternative QT study. 1685 |
| Ensacove (ensartinib hydrochloride) | 218171, 2024-12-18 152 | The approved dose is 225 mg once daily. The highest QT-assessment dose was 250 mg once daily (Study 101), with Cmax 384.8–385 ng/mL. This was reported as covering 0.9× the high clinical Cmax in Chinese patients (Study 28311) and 1.2× in global patients (Study 301); another review table reports 1.4× for Study 301. Separately, clinical ECG/modeling data extended to approximately 600–700 ng/mL, about 2× the mean steady-state Cmax at 225 mg daily. Thus, the documents contain differing descriptions of the exposure multiple depending on the comparison dataset. 1431 | At the 225-mg therapeutic dose in Study 301 (Cmax 276.7 ng/mL), predicted mean ΔQTcF was -4.83 ms (90% CI: -6.83 to -2.83); pooled analysis predicted -4.73 ms (90% CI: -6.31 to -3.15). At 250 mg in Study 101 (Cmax 263 ng/mL), predicted mean ΔQTcF was -4.10 ms (90% CI: -6.49 to -1.71). The FDA summary table similarly reported ΔΔQTcF -4.9 ms (90% CI: -6.4 to -3.4) at 225 mg in global Study 301 and -6.7 ms (90% CI: -8.7 to -4.7) at 250 mg. FDA concluded that a mean QTc increase >20 ms was not observed at the recommended dose. 1428 | Not adequately characterized | A standard TQT study was not used; FDA categorized the oncology program as an alternative QT assessment when a TQT study is not feasible. The assessment was limited because there was no positive control and no large exposure margin; therefore, FDA stated it could not definitively establish that ensartinib has no QTc effect. The highest assessed dose covered clinical exposures, rather than providing a substantial supratherapeutic margin. 1425 |
| Avmapki Fakzynja Co-Pack (Copackaged) (avutometinib potassium; defactinib hydrochloride) | 219616, 2025-05-08 117 | The approved regimen was avutometinib 3.2 mg twice weekly plus defactinib 200 mg twice daily. The highest QT-assessment doses were avutometinib 4 mg twice weekly (geometric-mean Cmax 323 ng/mL; 1.5-fold versus clinical/high clinical exposure) and defactinib 200 mg twice daily (Cmax 549 ng/mL; 1.2-fold versus clinical exposure but only 0.6-fold versus the high clinical exposure of 981 ng/mL, defined as a 2.2-fold increase with strong CYP3A4 inhibition). 1786 | At Cycle 1 Day 15, 4 hours after dose, the mean ΔQTcF was 1.8 ms (90% CI, -2.1 to 5.7) in the mutation cohort and 1.1 ms (90% CI, -2.8 to 5.0) in the wild-type cohort for the recommended combination. FDA concluded that the combination was not associated with a mean QTcF increase of ≥20 ms; however, without placebo, FDA stated it could not definitively conclude there was no QTc effect. 1783 | Not adequately characterized | A dedicated QT study was not conducted. The assessment was limited because RAMP-201 lacked a placebo control, so absence of any QTc effect could not be definitively established under ICH E14 Q&A 6.1; also, limited PK sampling in the relevant combination study precluded FDA's C-QTc analysis. There was no identified high-clinical-exposure scenario for avutometinib, whereas defactinib's high-exposure scenario with strong CYP3A4 inhibition was not fully covered (0.6-fold). 1791 |
| Ibtrozi (taletrectinib adipate) | 219713, 2025-06-11 113 | The recommended dose was 600 mg once daily fasting (steady-state Cmax 476 ng/mL). The anticipated high-exposure scenario was 600 mg with a high-fat meal, increasing Cmax 1.5-fold to 714 ng/mL. The highest mean exposure in the QT assessment was 600 mg QD on Day 15 (Cmax 643.2 ng/mL; 0.9-fold of that high-exposure scenario); 1200 mg QD yielded Cmax 918 ng/mL, but only one subject received that dose on Day 15. 1769 | The model predicted ΔQTcF of 12.9 ms (90% CI 10.3–15.6) at therapeutic 600 mg fasting; 20.5 ms (16.3–24.7) at the 1.5-fold high-fat-meal exposure; and 18.2 ms (14.5–22.0) at the highest mean observed QT-assessment exposure (600 mg QD Day 15, 643.2 ng/mL). The pooled analysis predicted 15.0 ms (11.91–18.09) at 800 mg and 26.82 ms (21.30–32.35) at 1200 mg. Thus, the upper 90% CI exceeded 10 ms at clinically relevant exposure. 1768 | QTc prolongation identified | A thorough-QT study was not used because this was classified as an alternative QT study when a thorough QT study is not feasible. Limitations included no placebo or positive control (therefore assay sensitivity was not applicable); exclusion of fed ECG/PK data from the C-QTc analysis; the applicant’s pooling of fed and fasted data potentially introducing bias; exclusion of U101 Cycles 2–3 ECGs; and only one subject at 1200 mg on Day 15. FDA’s independent analysis excluding fed data was similar to the applicant’s. The high-fat-meal exposure was modeled because it was the anticipated high clinical exposure scenario. 1772 |
| Zegfrovy (sunvozertinib) | 219839, 2025-07-02 110 | The highest QT-assessment dose was 300 mg once daily, with observed Cmax 523 ng/mL (Cycle 3 Day 1). This was 0.84× the 300-mg clinical Cmax (619 ng/mL) and 0.62× the high-clinical-exposure Cmax (842 ng/mL, based on a 1.36-fold Cmax increase in moderate hepatic impairment). The approved recommended dose is 200 mg; label wording reports assessment at 1.5× that dose. 1962 | At the high clinical exposure scenario (842 ng/mL), model-predicted ΔQTcF was 0.4 ms (90% CI −1.7 to 2.5 ms); at the 300-mg clinical Cmax (619 ng/mL), 0.7 ms (90% CI −0.8 to 2.3 ms). The review states a mean QTc effect >10 ms could be excluded across the full observed concentration range; by-time 90% upper bounds were <10 ms at all qualifying timepoints except one 10.8-ms estimate based on 6 patients. 1965 | Not adequately characterized | No dedicated thorough-QT study was conducted; an alternative assessment was used because the highest QT-assessment dose was the therapeutic dose. Assessment was limited by absence of a positive control and failure to achieve at least a twofold margin over high clinical exposure; FDA therefore was reluctant to conclude that sunvozertinib has no QTc effect. Integrated nonclinical risk assessment was not performed. 1958 |
| Hernexeos (zongertinib) | 219042, 2025-08-08 132 | The highest QT-assessment dose was 360 mg once daily (three times the recommended 120-mg dose), with mean Cmax 7,150 nM. This was approximately 2.6-fold the clinical Cmax at 120 mg once daily and approximately 2-fold the high clinical-exposure scenario with strong CYP3A4/P-gp inhibition. 1988 | Exposure-response estimates for ΔQTcF were 0.5 ms (90% CI −0.2 to 1.2) at 120 mg once daily (2,730 nM) and 1.8 ms (90% CI 0.5 to 3.2) at 360 mg once daily (7,150 nM). FDA concluded that zongertinib did not cause mean QTc prolongation ≥20 ms, although, without placebo control, FDA could not conclude there was no QTc effect. 1988 | Not adequately characterized | A formal placebo-controlled QT/QTc study was not feasible for ethical reasons in patients. The assessment was limited by the absence of placebo control (therefore no conclusion of no QTc effect), no positive control/assay sensitivity in the clinical analysis, and unevaluated moderate/severe hepatic impairment. Integrated nonclinical support was not accepted because the hERG study had best-practice deviations and no reference-drug comparison, while the in-vivo QT study lacked a positive control and sensitivity information. 1996 |
| Inluriyo (imlunestrant tosylate) | 218881, 2025-09-25 136 | The approved dose is 400 mg once daily (mean steady-state Cmax 141 ng/mL). The highest clinical QTc-assessment dose was 1200 mg once daily (3 times the approved dose), with Cmax 253 ng/mL, 1.8-fold above clinical exposure. The approved labeling characterizes the assessment as 2 times the mean maximum concentration observed with the approved recommended dose. 1736 | The reviewer’s concentration-QTcF model predicted ΔQTcF of 1.1 ms (90% CI −0.6 to 2.8) at 400 mg/Cmax 141.9 ng/mL and 0.6 ms (90% CI −2.0 to 3.3) at 1200 mg/Cmax 253 ng/mL; thus, the upper 90% confidence bounds were well below 10 ms. FDA concluded that mean QTc prolongation ≥20 ms was not demonstrated, but absence of any QTc effect could not be concluded because the studies lacked a positive control. 1739 | Not adequately characterized | A standard dedicated thorough-QT assessment was not performed; the submission used the alternative ICH E14 Q&A 6.1 pathway. The clinical study lacked both placebo and positive control, so FDA was reluctant to conclude no QTc effect. Moreover, FDA did not consider the integrated nonclinical assessment negative: in the 3-month monkey study, QTc increased by approximately 20 ms after 10 hours post-dose at 600 mg/kg at Weeks 4, 8, and 15. Consequently, FDA stated that the available data did not support concluding a low likelihood of delayed-repolarization proarrhythmic risk. 1744 |
| Komzifti (ziftomenib) | 220305, 2025-11-13 100 | The highest dose in the QTc assessment was the approved therapeutic dose, 600 mg once daily. Study participants in the QTc assessment were estimated to have approximately 50% of the clinical Cmax because strong CYP3A4 inhibitors could approximately double Cmax but were generally prohibited in the study. At 600 mg once daily, mean steady-state Cmax was 881 ng/mL; a high-fat meal could increase Cmax approximately 4-fold (expected high Cmax about 3524 ng/mL). 2448 | FDA found a concentration-dependent QTc increase. In 133 patients at 600 mg once daily, the largest predicted mean QTc increase was 7.7 ms, with upper CI 12.6 ms; 8% (10/133) had both QTcF >500 ms and a >60-ms increase from baseline. The applicant's model predicted that the 90% upper confidence bound would exceed 10 ms at approximately 865 ng/mL and exceed 20 ms at approximately 1380 ng/mL. FDA considered the concentration-QTc findings inconclusive as a standalone assessment because sparse ECG sampling did not support assessment of delayed QTc effects. 2468 | QTc prolongation identified | A dedicated thorough-QT study was not used; an alternative patient-study assessment was agreed because the development program was in relapsed/refractory AML. Its interpretability was limited by only 4-9 subjects at post-dose steady-state ECG time points at 600 mg (2-4 at 800 mg), sparse ECG timing, and only one time-matched PK/ECG time point in the full study population. FDA added a warning because of the concentration-dependent effect, observed outliers, potential exposure increases from CYP3A inhibition or food, hypokalemia, and concomitant QT-prolonging supportive medications. 2448 |
| Hyrnuo (sevabertinib) | 219972, 2025-11-19 105 | The approved regimen was 20 mg twice daily. The highest QTc-assessment dose was 60 mg once daily, covering anticipated therapeutic Cmax by 2.2-fold. The label describes assessment at 2 times the maximum recommended dose (80 mg total daily dose). 2380 | At steady-state Cmax after 60 mg once daily, the largest predicted mean QTc increase was 3.9 ms (90% CI, 2.0 to 5.8 ms). At 20 mg twice daily, the predicted mean increase was 1.5 ms (90% CI, 0.4 to 2.6 ms). The model excluded a mean QTcF increase of 20 ms or more; the upper 90% CI remained below 20 ms even at the highest observed concentration (3,519 µg/L; about 4-fold the geometric-mean Cmax at 20 mg twice daily). 2373 | Not adequately characterized | A dedicated thorough-QT study was not used; the FDA classified the assessment as an alternative QT study. Although the patient-study exposure-response analysis excluded a mean increase of 20 ms or more, Study 21607 lacked both placebo and positive control, so FDA stated it could not conclude that sevabertinib has no QTc effect. Higher-exposure scenarios with moderate CYP3A4 inhibition or severe hepatic impairment had not been characterized. 2370 |
| Bysanti (milsaperidone) | 220358, 2026-02-20 99 | The studied dose was iloperidone 12 mg twice daily, which is the maximum recommended BYSANTI maintenance dose (12 mg twice daily; 24 mg/day). The documents do not provide a numeric exposure multiple relative to maximum clinical exposure. Combined CYP2D6/CYP3A4 inhibition was evaluated to augment exposure. 2433 | At iloperidone 12 mg twice daily, QTc prolongation was 9 msec. With combined CYP2D6 and CYP3A4 inhibition (paroxetine 20 mg once daily plus ketoconazole 200 mg twice daily), the mean QTcF increase from baseline was about 19 msec. No 90% confidence interval or <10-ms threshold analysis is reported in the provided documents. 2433 | QTc prolongation identified | A dedicated thorough-QT study, concentration-QTc model, exposure multiple, and confidence-interval analysis are not described in the provided rows. The approval relied on prior Agency findings for Fanapt (iloperidone) and comparative-bioavailability studies establishing a scientific bridge, because milsaperidone and iloperidone rapidly interconvert in vivo. 2443 |
| Veppanu (vepdegestrant) | 219835, 2026-05-01 111 | Patients received the recommended 200 mg once-daily dose, but the QT substudy achieved only 0.8-fold of clinical Cmax; thus, the high clinical exposure was not covered. A strong CYP3A4 inhibitor was anticipated to increase Cmax about 1.5-fold. 2353 | At 200 mg once daily, the QT substudy by-time result was mean ΔQTcF 11.1 ms (90% CI 8.2–14.0) at Cycle 2 Day 1 predose; FDA's overall summary reported a mean QTcF change of 12 ms with upper 90% CI of 15 ms. The upper confidence bounds exceeded 10 ms but were below 20 ms. 2353 | QTc prolongation identified | This was an alternative QT study when a thorough-QT study was not feasible. Sampling was sparse (predose and 5–7 hours postdose), did not establish absence of QTc hysteresis or reliably capture maximal QTc effect/Cmax, and therefore FDA reviewers did not conduct their own C-QTc analysis. The study also did not cover the high-exposure scenario. 2353 |
| Beqalzi (sonrotoclax) | 220711, 2026-05-13 95 | The maximum recommended regimen was 320 mg once daily with a low-fat meal (anticipated Cmax 352.7 ng/mL). The highest exposure included in the QTc assessment was a weekly-ramp-up 320-mg-QD cohort, with geometric-mean Cmax 400 ng/mL—1.13-fold the low-fat-meal therapeutic Cmax, but only 0.71-fold the high-clinical-exposure scenario (Cmax 564.3 ng/mL with a high-fat meal). 2178 | FDA concentration-QTc analysis predicted a mean ΔQTcF of 7.1 ms (90% CI 0.1 to 14.1 ms) at 320 mg once daily with a low-fat meal (Cmax 352.7 ng/mL). At the highest QT-assessment exposure (400 ng/mL; n=5), the predicted mean ΔQTcF was 7.9 ms (upper 90% CI 15.9 ms). The predicted high-fat-meal scenario (564.3 ng/mL) was 10.9 ms (90% CI −0.3 to 22.1 ms), but this exposure was not covered by the clinical QT dataset. 2174 | Not adequately characterized | A thorough-QT study in healthy subjects was not performed; the sponsor used patient C-QTc analysis in lieu of such a study. The assessment was limited because Study 101 had no placebo or positive control, and the highest measured QT-assessment exposure covered only 0.71-fold of the high-clinical-exposure scenario. FDA stated that, at the maximum recommended dose, the analysis did not exclude a mean QTc increase >20 ms under ICH E14/S7B Q&A 6.1, and labeling states that higher-concentration effects are insufficiently characterized. 2174 |
| Revtorpyk (gedatolisib) | 219908, 2026-07-14 107 | The approved dose is 180 mg weekly; doses through 319 mg were studied (1.8 times the recommended dose per label). The pooled 222/266/319-mg QT-assessment cohorts had mean Cmax 16,113.7 ng/mL versus 13,753.5 ng/mL at the therapeutic regimen, approximately 1.2-fold clinical Cmax. However, the sponsor did not characterize a high-clinical-exposure scenario and anticipated up to a 2-fold exposure increase with moderate/severe hepatic impairment or strong P-gp inhibitors. 2528 | C-QTcF modeling did not suggest large mean QTcF increases. At 180 mg (Cmax 13,753.5 ng/mL), predicted ΔQTcF was −14.6 ms (90% CI −18.5 to −10.6); at pooled 222–319 mg (16,113.7 ng/mL), it was −16.9 ms (90% CI −19.5 to −12.4). The reviewer also reported that the overall upper bound of the 90% CI was below 10 ms. FDA’s pharmacology/PK summary states that an effect on ΔQTcF exceeding 20 ms could be excluded over observed concentrations up to about 63,000 ng/mL. 2530 | Not adequately characterized | A dedicated thorough QT study was not performed; FDA categorized the approach as an alternative QT study when a thorough QT study was not feasible. The review notes that, without adequate placebo and positive controls, FDA was reluctant to conclude that gedatolisib has no QT effect. Assessment at high clinical exposure was limited because the sponsor had not characterized that scenario; the evaluated high-dose cohorts covered only about 1.2-fold clinical Cmax, whereas up to 2-fold higher exposure was anticipated in hepatic impairment or with strong P-gp inhibitors. 2528 |
| Jideytro (zidesamtinib) | 220185, 2026-07-22 102 | The recommended dose and highest dose in the QT assessment was 100 mg once daily. The anticipated high clinical exposure was a 1.79-fold Cmax increase with strong CYP3A4 inhibition (zidesamtinib Cmax 1,672 ng/mL versus 934 ng/mL at 100 mg); the review concluded that the highest QT-assessment exposure covered anticipated therapeutic exposure, although an exact Cmax ratio for the Phase 2 QT dataset could not be calculated because intensive PK was not collected. Nonclinically, QTc prolongation occurred in dogs at 3.6-fold high clinical exposure. 2586 | At 100 mg once daily, the largest mean placebo-unadjusted/by-timepoint QTcF increase was 13.2 ms (90% CI 7.8–18.6) at Cycle 1 Day 15, 6 hours post-dose, in Phase 2. FDA also summarized this as 13 ms with a 90% CI upper bound of 19 ms. Reviewer M9 C-QTc modeling predicted ΔQTcF of 7.0 ms (90% CI 5.5–8.4) at steady-state M9 concentration and 10.6 ms (8.7–12.5) at high clinical M9 exposure in low-body-weight patients. 2579 | QTc prolongation identified | A dedicated thorough-QT study was not performed; FDA used the alternative-QT-study pathway because a thorough QT study was not feasible. Assessment was limited by sparse/time-matched PK/ECG sampling: timing did not permit robust exposure-response analysis, Phase 1 Cycle 1 Day 15 sampling missed Tmax, and the collection schedule did not support robust evaluation of the no-hysteresis assumption for the primary linear mixed-effects C-QTc model. Earlier integrated nonclinical assessment was also inadequate: M9 hERG testing was unavailable, the dog study lacked positive-control sensitivity data, and the high clinical exposure was initially uncertain. 2592 |
| Rasonque (daraxonrasib) | 220910, 2026-08-26 271 | The recommended dose is 300 mg once daily. Pharmacokinetics were evaluated over 80 mg (0.27 times the recommended dose) to 300 mg; no QT-specific exposure multiple or supratherapeutic exposure was reported. 2605 | At the recommended dosage, a mean increase in the QTc interval >20 msec was not observed. 2605 | Not adequately characterized |
Integrated nonclinical + clinical assessment (18)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Livmarli (maralixibat chloride) | 214662, 2021-09-29 225 | In MRX-102, a 100-mg fasted single dose produced Cmax 3.05 ng/mL (approximately 4.3 nM) and provided approximately 3-fold coverage of the maximum recommended therapeutic dose; the maximum recommended dose was stated as up to 26.5 mg. The clinical PK review also notes the highest observed concentration in pediatric patients receiving 400 µg/kg once daily was 5.93 ng/mL. 537 | There were no meaningful ECG changes in MRX-102: mean change from baseline in QTcF was not clinically significant and showed no dose-dependent pattern. Exploratory PK/ECG analysis found no positive exposure–QTc relationship; no subject had QTcF >480 ms or a QTcF increase from baseline >60 ms. Across completed studies, including doses up to a 500-mg single dose, there were no clinically meaningful QT-interval or other ECG-parameter changes. No quantified mean QTc effect or 90% CI was reported in the retrieved rows. 537 | No clinically relevant prolongation | The TQT study was waived because maralixibat is minimally absorbed, systemic exposure was very low even at the 100-mg supratherapeutic dose (~3 times the maximum recommended dose; Cmax about 4 nM), high exposure from intrinsic or extrinsic factors was unlikely, hERG inhibition was not significant with a >5,920-fold hERG safety margin, nonclinical cardiovascular studies had >2,600-fold exposure margin at the high dog exposure, and clinical ECG data did not identify QT risk. The planned concentration-QTc analysis was conditional on substantial exposure and was waived when low exposure was observed. 535 |
| Voxzogo (vosoritide) | 214938, 2021-11-19 223 | The pivotal ECG assessment evaluated the maximum approved/recommended dose, 15 mcg/kg subcutaneously once daily for 52 weeks, with steady-state Cmax reported as 5.8 ng/mL (elsewhere 7.18 ng/mL at Day 1). The Phase 3 concentration-QTc model prediction at 5.7 ng/mL was therefore approximately therapeutic Cmax (not a supratherapeutic multiple). The maximum clinical dose studied was 30 mcg/kg once daily. Nonclinically, 50 mcg/mL in the hERG assay was >8,620-fold the therapeutic Cmax; in monkeys, 200 mcg/kg produced Cmax 52.5 ng/mL versus human therapeutic exposure 5.8 ng/mL. 318 | FDA concentration-QTc analysis predicted ΔΔQTcF of 4.2 ms at 5.7 ng/mL, with 90% CI 1.9 to 6.5 ms (upper bound <10 ms). No subject in the 52-week pivotal study had QTc prolongation >450 ms, and FDA concluded that no significant QTc-prolongation effect was detected. In monkeys, QTc shortened (maximum −8%), rather than prolonged. 311 | No clinically relevant prolongation | A dedicated TQT study was waived because vosoritide has sequence homology to endogenous CNP and is a large biologic peptide, making cardiac-ion-channel effects very unlikely; its nonclinical program indicated low QT-prolongation potential (including no statistically significant hERG inhibition at an 8,620-fold Cmax multiple); and early clinical development showed no signal. The clinical study had neither a separate positive control nor required multiples of clinically relevant exposure; FDA considered the integrated nonclinical/clinical assessment adequate. The review also stated that no clinical scenarios were known to increase vosoritide exposure beyond therapeutic-dose exposure. 314 |
| Cytalux (pafolacianine sodium) | 214907, 2021-11-29 224 | Clinical ECG data were from the ovarian-cancer safety population (QTc baseline n=147; Day 7 change-from-baseline n=109). The recommended dose was 0.025 mg/kg. Dog ECG evaluations used 0.9, 9.3, and 13.9 mg/kg (approximately 36-, 372-, and 556-fold the recommended mg/kg dose, respectively); however, the documents do not provide a clinical exposure multiple or an exposure-matched QT assessment. 582 | In the combined ovarian-cancer ECG dataset, mean QTc change from baseline at Day 7 was 0.16 ms (SD 26.393; n=109). No patient had QTc >500 ms. One Study 006 subject had QTc 500 ms on Day 7 versus 420 ms at baseline; this was considered abnormal but not clinically significant. In dogs, no effects on QT or QTcV were observed at any tested dose. 583 | No clinically relevant prolongation | A QTc waiver was recorded in the regulatory-interactions table (November 9, 2020). The retrieved documents do not state the rationale for that waiver, and they do not provide the final Prescribing Information section 12.2 Cardiac Electrophysiology wording. 603 |
| Mounjaro Kwikpen (tirzepatide) | 215866, 2022-05-13 212 | The maximum recommended/proposed clinical dose was 15 mg once weekly. The C-QTc model predicted effects at mean 15-mg steady-state Cmax of 1,560 ng/mL; monkey studies showed no QTc change at up to 2.6-fold clinical exposure (with clinical 15-mg steady-state Cmax reported as 1,990 ng/mL). FDA had previously noted that the original three-study C-QTc sampling did not cover steady-state Cmax at 15 mg once weekly. 408 | No QTcF prolongation or concentration-QTc relationship was identified in the Phase 1/2 analyses. In the Phase 3 program, no participant had QTc >500 ms or an increase from baseline >60 ms; no clinically meaningful differences in QTc abnormalities were apparent across placebo-controlled studies or among 5-, 10-, and 15-mg dose groups. A numerical model-estimated mean effect or 90% CI upper bound was not provided in the retrieved rows. 413 | No clinically relevant prolongation | A dedicated TQT study was considered challenging because tirzepatide has an approximately 5-day half-life and requires titration to reach steady-state exposure at the highest dose. IRT also considered that peptides composed of naturally occurring amino acids have a low likelihood of direct ion-channel interactions; however, because tirzepatide releases a free linker with limited systemic-exposure information, FDA reviewed the submitted nonclinical and clinical data rather than relying solely on that general peptide rationale. 410 |
| Vtama (tapinarof) | 215272, 2022-05-23 218 | The maximal-use study applied 1% cream once daily to 21–46% BSA (mean daily dose 5.23 g; mean BSA 27.2%), versus the proposed/recommended-use BSA of approximately 8%; FDA stated this produced exposures higher than therapeutic exposures at proposed recommended doses. Day-1 mean Cmax was 0.90 ng/mL. Concentration-QTc analysis excluded a QTcF effect >10 ms through observed concentrations of approximately 4,600 pg/mL. The nonclinical hERG safety margin was 105,449-fold versus free Cmax (hERG IC50 5.1 µM; free Cmax 0.0123 ng/mL). 396 | By-time analysis found negative mean ΔQTcF at every time point (−7.2 to −1.1 ms); the largest 90% CI upper bound was 3.90 ms. Concentration-QTc analysis found no clinically relevant effect and excluded ΔQTcF >10 ms within observed concentrations up to approximately 4,600 pg/mL. No participant had QTcF >500 ms or ΔQTcF >60 ms. 396 | No clinically relevant prolongation | A formal thorough-QT study in healthy volunteers was considered of limited utility because intact skin produces considerably lower tapinarof absorption than clinical diseased-skin use, so healthy-volunteer exposures would not reflect clinical scenarios. The maximal-use patient study was considered adequate because it achieved higher-than-therapeutic exposures and there were no anticipated clinical scenarios, including drug interactions or organ impairment, expected to increase exposure. The hERG assay had methodological departures from best practices (including room temperature, slow stimulation, and stock-solution rather than recording-chamber concentration verification), but FDA considered these not material given the very large hERG margin. 394 |
| Qalsody (tofersen) | 215887, 2023-04-25 256 | The therapeutic/maximum approved regimen was 100 mg intrathecally every 14 days for three loading doses, then every 28 days for maintenance. High clinical exposure was considered similar to therapeutic exposure because intrinsic/extrinsic factors were not predicted to meaningfully affect exposure. At the largest geometric-mean Cmax in Part C (731 ng/mL), the modeled QTc result was assessed; this was considered sufficient to characterize therapeutic exposure. No supratherapeutic clinical multiple was defined. The hERG safety margin was >16,576-fold (9% inhibition at 34 μM); in vivo, tofersen was tolerated at an exposure ratio of 48-fold with 35 mg, although ECGs in that study were not informative. 863 | At 731 ng/mL (largest geometric-mean Cmax in Part C), placebo-corrected change from baseline QTcF (ΔΔQTcF) was 0.3 ms, with a 90% CI of −4.7 to 5.2 ms. Across the 5th–95th percentiles of observed tofersen concentrations, both the modeled mean and upper confidence bound were below 10 ms. No subject had QTcF >500 ms or ΔQTcF >60 ms. 863 | No clinically relevant prolongation | The sponsor requested a TQT waiver based on no cardiovascular safety signal in nonclinical and clinical studies and the limited QT-prolongation potential of a similar antisense oligonucleotide class. FDA had recommended the integrated nonclinical-clinical approach. A conventional high-exposure scenario was not defined because tofersen is an intrathecal antisense oligonucleotide and exposure was not expected to be meaningfully affected by intrinsic or extrinsic factors. The in-vivo toxicology ECG assessment was limited: concentrations at ECG collection times were subtherapeutic and ECGs were not collected at Tmax. 866 |
| Paxlovid (Copackaged) (nirmatrelvir; ritonavir) | 217188, 2023-05-25 177 | The clinical QT assessment used nirmatrelvir 2250 mg split into three 750-mg doses with ritonavir 100 mg, producing mean Cmax 15.9 µg/mL. This was 1.47-fold the sponsor-defined high clinical exposure (10.8 µg/mL in severe renal impairment with 150/100 mg plus food); the current label describes the assessment as at 3 times steady-state Cmax at the recommended dose. 707 | At 15,943.7 ng/mL (approximately the 2250-mg mean Cmax), model-predicted mean ΔΔQTcF was 0.5 ms (90% CI, -2.4 to 3.4 ms); all upper 90% CI bounds across the observed concentration range were well below 10 ms. No subject had QTcF >450 ms or a >30-ms change from baseline. Supporting nonclinical results included no QTc prolongation in monkeys at exposures expected to exceed high clinical exposure and hERG inhibition of 12% at 300 µM (hERG safety margin >44-fold). 699 | No clinically relevant prolongation | A separate dedicated TQT/positive-control study was not performed because FDA accepted the integrated clinical and double-negative nonclinical assessment under ICH E14 Q&A 5.1. The Part 5 clinical exposure was only 1.47-fold high clinical exposure—below the ≥2-fold exposure criterion to waive a positive control—so negative hERG and in-vivo QT findings were used to support interpretation. Earlier ECG monitoring in Phase 2/3 trials was discontinued after preliminary Part 5 and sentinel-cohort ECG data and an external monitoring committee found no cardiac safety signal. 705 |
| Rivfloza (nedosiran sodium) | 215842, 2023-09-29 257 | Monkeys received three subcutaneous doses of 30 or 300 mg/kg on Days 1, 4, and 10. The estimated hERG IC50 safety margin was >390-fold versus unbound maximum plasma Cmax in patients receiving the maximum recommended dose, 160 mg once monthly. 1043 | Safety pharmacology studies in monkeys showed no QT or QTcB prolongation. Clinical exposures were not expected to cause meaningful hERG-related QT prolongation. 1043 | No clinically relevant prolongation | No explicit rationale for not conducting a standard dedicated clinical QT assessment is provided in the retrieved document; the stated basis is negative monkey QT/QTcB findings and a >390-fold hERG safety margin relative to maximum-dose clinical exposure. 1043 |
| Wainua (Autoinjector) (eplontersen sodium) | 217388, 2023-12-21 171 | The assessed dose was 2.7 times the maximum recommended WAINUA dose. The label describes healthy-volunteer single doses of 45–120 mg, corresponding to 1–2.7 times the recommended dose. 1292 1292 | Clinically significant QTc interval prolongation was not observed at 2.7 times the maximum recommended dose. No mean QTc effect or confidence-interval bound was provided in the retrieved rows. 1292 1292 | No clinically relevant prolongation | The applicant requested a thorough-QT-study waiver. FDA's QT-IRT determined that nonclinical assessments could substitute for a TQT study because the integrated data showed eplontersen does not cause clinically significant QTc prolongation; the Agency later stated that clinical ECGs and integrated nonclinical assessments could serve as the substitute under ICH E14 Q&A 5.1. 1289 1289 |
| Voydeya (danicopan) | 218037, 2024-03-29 154 | The labeled clinical assessment used a single 1200-mg dose, producing approximately 2 times the peak concentration following the maximum recommended 200-mg three-times-daily regimen. The review separately describes this dose as 6 times the maximum recommended dose based on Cmax. 1379 | No clinically relevant QTc prolongation was observed. No mean QTc effect or 90% confidence-interval bound was provided in the retrieved rows. 1379 | No clinically relevant prolongation | |
| Flyrcado (flurpiridaz f-18) | 215168, 2024-09-27 199 | The phase 1 C-QTc study used approximately 2.88–2.98 µg, about 5-fold below the proposed maximum total cold mass dose of ≤14 µg (approximately 0.2× maximum). The reviewer estimated that 14 µg would yield mean plasma Cmax about 300 pg/mL (0.815 nM), versus 29.9 pg/mL after 2.88 µg. In dogs, the ECG NOAEL of 50 µg/kg was approximately 121-fold the surface-area-adjusted maximum human dose; the hERG margin was >10,000-fold the estimated maximum plasma concentration (~1 nM). 1449 | The submitted phase 1 model predicted ΔQTcF of −7.6 ms at parent flurpiridaz mean Cmax (29.9 pg-equivalent/mL) and −1.1 ms at metabolite mean Cmax (11.4 pg-equivalent/mL), but FDA considered this analysis uninterpretable. The phase 3 ECG data supported excluding a large mean QTc increase and had few significant QTc outliers. No statistically specified mean effect or 90% CI upper bound was reported in the provided documents. The highest QTc among participants with a QT-related adverse event was 477 ms; four serious-event cases had QTc <470 ms and baseline increase <30 ms. 1447 | No clinically relevant prolongation | A standard formal QT assessment was not conducted in the context of an infrequently administered microdose radiolabeled imaging product (maximum cold mass ≤14 µg, below the FDA microdose threshold of 100 µg). The phase 1 plasma C-QTc assessment was limited/not interpretable because the compound intentionally accumulates in cardiac myocytes by binding mitochondrial complex I, making plasma concentration an unsuitable exposure surrogate, and because the tested cold dose was about 5-fold below the marketed maximum. 1445 |
| Tryngolza (Autoinjector) (olezarsen sodium) | 218614, 2024-12-19 143 | A supratherapeutic 120-mg single dose (1.5 times the 80-mg maximum recommended dose) was studied in Phase 1 study ISIS-678354-CS1. 1842 | The integrated assessment concluded that olezarsen did not prolong QTcF by ≥10 ms; at 1.5 times the maximum recommended dose, clinically significant QTc prolongation was not observed. 1841 | No clinically relevant prolongation | The integrated nonclinical-plus-clinical ECG risk assessment was used as a substitute for a dedicated thorough QT study. Nonclinical studies were negative for QT effects. 1841 |
| Qfitlia (fitusiran sodium) | 219019, 2025-03-28 133 | Evidence supported lack of QTc prolongation through 80 mg once monthly (QM), the highest dose studied. The approved starting regimen is 50 mg every 2 months, with modified regimens including up to 50 mg QM. 1986 | The nonclinical and clinical totality of evidence indicated that fitusiran was not associated with QTc prolongation up to 80 mg QM. No numerical mean QTc effect or confidence interval was provided in the retrieved documents. 1986 | No clinically relevant prolongation | A human TQT study was not conducted because nonclinical and clinical data were considered totality-of-evidence support that fitusiran is not associated with QTc prolongation up to 80 mg QM. 1986 |
| Dawnzera (Autoinjector) (donidalorsen sodium) | 219407, 2025-08-21 120 | The C-QTc analysis had a Cmax of 592 ng/mL (CV 38%), approximately 0.7-fold the mean Cmax (867 ng/mL) in the lowest-body-weight clinical group (37–68.5 kg); individual observations reached approximately 0.9-fold of that group’s Cmax. FDA considered this adequate given no concentration-QTc relationship, an approximately 62-fold in-vivo QTc assessment margin, and no hERG signal. 2120 | No concentration-QTc relationship was observed. The retrieved documents do not provide a numerical mean QTc effect or 90% confidence-interval upper bound. Nonclinically, donidalorsen inhibited hERG current by 0.5% and 1.9% at 30 and 300 µM, respectively; estimated hERG IC50 was greater than 300 µM. 2120 | No clinically relevant prolongation | FDA granted a thorough-QT-study waiver because the QT/QTc risk assessment showed low risk of QTc prolongation and could substitute for a thorough QT study. The clinical C-QTc dataset did not attain high exposure multiples: its mean Cmax was about 0.7-fold that of the lowest-body-weight clinical group. FDA nevertheless found coverage adequate because there was no C-QTc relationship, nonclinical in-vivo QTc margin was approximately 62-fold, hERG showed no signal, and individual observations reached approximately 0.9-fold of the low-body-weight-group Cmax. 2125 |
| Cardamyst (etripamil) | 218571, 2025-12-12 145 | The highest QT-assessment dose was a single 140 mg intranasal dose (2× the 70-mg maximum recommended single dose). Its mean etripamil Cmax was 184 ng/mL, versus 135 ng/mL for the sponsor’s high clinical-exposure scenario of two 70-mg doses 10 minutes apart—1.4-fold coverage. FDA also stated that this highest study dose covered the high clinical exposure of the newly recognized major metabolite Unk10. 2279 | No significant QTc prolongation was detected with single doses up to 140 mg. The clinical cardiovascular study found decreases in QTcF, and exposure-response analyses suggested a QT-shortening effect. A numerical mean QTc effect or 90% confidence-interval upper bound was not provided in the retrieved rows. 2282 | No clinically relevant prolongation | The standard TQT study was waived because large heart-rate increases (>10 bpm) at all dose levels confounded QTc estimates, making conventional QTc assessment challenging. FDA instead recommended comparative ion-channel testing with verapamil and the major metabolite MSP-2030, plus clinical ECG data. For Unk10, no additional QTc study was recommended despite unknown pharmacokinetics because the 140-mg clinical study dose covered its high clinical exposure under the proposed regimen. 2280 |
| Adquey (difamilast) | 219474, 2026-02-12 119 | The phase 3 QTc substudy was markedly underexposed relative to high/maximal-use clinical exposure: mean steady-state Cmax 0.5 ng/mL versus 14 ng/mL in the maximal-use study (approximately 1/28th, or ~3.6%, of that exposure). The dog in-vivo study found no QTc prolongation at 98-fold the Cmax from the maximal-use study. 2202 2199 2202 | In the phase 3 QTc substudy, the maximum upper bound for ΔQTcF was <10 ms; C-QTc models showed no significant concentration-QTc relationship and predicted upper bounds of the 90% CI were <10 ms. However, the QT-IRT concluded the substudy did not adequately characterize QTc because exposure and disease severity were not representative of the intended population. 2201 2207 2201 | No clinically relevant prolongation | A conventional TQT trial was not conducted because supratherapeutic systemic exposure was considered infeasible with topical difamilast. The QTc substudy was limited by lower BSA involvement and substantially lower exposure than maximal use. Despite the QT-IRT’s recommendation for a dedicated study/PMR, the PMR was waived based on the large hERG safety margin (7,931-fold), absence of QTc prolongation in dogs at 98-fold clinical Cmax, clinical safety data, lack of accumulation, and PDE-4 class experience. 2208 2207 2208 |
| Lynavoy (linerixibat) | 220295, 2026-03-17 101 | The review states that there was a low risk of QT prolongation. No mean QTc effect, confidence interval, or numerical QTc threshold/effect is reported in the provided rows. 2272 | No clinically relevant prolongation | A thorough-QT study was waived/agreed not to be performed because linerixibat has exceedingly low systemic exposure from minimal absorption (absolute oral bioavailability 0.05%); measurable plasma concentrations were sparse and often below quantification. The drug acts locally in the GI tract, has negligible metabolism/no major human-specific metabolites, and the review cites low QT risk based on nonclinical and clinical safety data. 2272 | |
| Foundayo (orforglipron calcium) | 220934, 2026-04-01 92 | The highest clinical QT-assessment dose was 45 mg once daily (Cmax 204 ng/mL), which covered the anticipated high clinical-exposure scenario of 194 ng/mL (approximately 1.05-fold). The final label describes assessment at 1.4 times the mean maximum concentration produced by the maximum recommended 17.2-mg once-daily dose. 2237 | At 45 mg once daily, model-predicted ΔΔQTcF was 2.7 ms (90% CI, -2.2 to 7.5 ms); at the high clinical-exposure scenario, it was 2.6 ms (90% CI, -2.1 to 7.4 ms). The exposure-response analysis showed no significant concentration-dependent QTcF effect, and the upper bound of the two-sided 90% CI was <10 ms at the highest exposure (geometric-mean Cmax 218 ng/mL for 45 mg). 2228 | No clinically relevant prolongation | A formal thorough-QT study was not conducted because the clinical concentration-QTc assessment was accepted as a substitute when paired with the integrated nonclinical risk assessment. The clinical study had no positive control, but its assessment was supported under ICH E14 Q&A 5.1 by negative hERG and in-vivo QT findings. Heart-rate increases of approximately 10–15 bpm were a limitation requiring consideration; FDA judged the increase slow enough that QTcF was acceptable, and also reviewed a one-stage correction analysis. Small cohort sizes produced wide by-time confidence intervals. 2229 |
Routine ECG monitoring only (7)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Ztalmy (ganaxolone) | 215904, 2022-03-18 207 | In Study 3001 double-blind treatment, the reviewer found no differential QTcF effect versus placebo. At week 5, ganaxolone mean/median change from baseline was -1.5/1.5 ms (maximum 26 ms); at week 17 it was 4.9/5.5 ms (maximum 60 ms). The 60-ms observation was considered an outlier, and the reviewer stated the findings did not reveal a significantly prolonged QT. No model-based estimate, 90% confidence-interval upper bound, or exposure multiple is provided in the rows. 350 | Not adequately characterized | FDA stated that the submitted data were not adequate to characterize the risk of QTc prolongation with oral ganaxolone. Therefore, the QT-IRT recommended a thorough-QT trial, which was imposed as a postmarketing requirement; the original approval letter scheduled final-report submission for December 2022. 354 | |
| Xenoview (xenon xe-129 hyperpolarized) | 214375, 2022-12-23 231 | QTc interval (Fridericia) changes from baseline qualifying as outliers occurred in 2 subjects (5%) overall at 1 hour and at 24 hours after the final dose; no clear safety signal was identified through the ECG data. 2650 | No clinically relevant prolongation | No formal QT study was needed or performed. The retrieved row does not provide a further rationale. 2650 | |
| Ojemda (tovorafenib) | 217700, 2024-04-23 161 | Assessed at the recommended dosage: 380 mg/m² orally once weekly, not to exceed 600 mg. No supratherapeutic dose or exposure multiple relative to the recommended/high clinical exposure is reported in the retrieved rows. 1476 | At the recommended dosage, a mean increase in the QT interval >20 milliseconds was not observed. No mean estimate, confidence interval/upper bound, or result versus a 10-ms threshold is provided. 1476 | Not adequately characterized | No rationale for omission, waiver, or limitation of a standard QT assessment is stated in the provided rows. 1476 |
| Rytelo (imetelstat sodium) | 217779, 2024-06-06 159 | No formal QT exposure multiple relative to the maximum recommended or high clinical exposure was reported. The document states that nonclinical safety-pharmacology measures, including ECG activity, showed no effect at imetelstat plasma concentrations >2.6-fold the Cmax in subjects with MDS; this is not a completed clinical QT assessment. 1655 | No interpretable formal QTc effect estimate (mean change or 90% CI) was reported. FDA reported QT information for only one MDS3001 patient, with baseline QTcF 423 ms. An episode of QTc prolongation was also reported in one treated patient, without quantitative details. 1653 | Not adequately characterized | The standard thorough-QT assessment was not completed for approval because the dedicated randomized placebo-controlled QTc substudy was ongoing and its report remained pending FDA review. FDA found available QT information limited to a single patient and stated that no definitive conclusions could be drawn regarding imetelstat's effect on cardiac events diagnosed by ECG because of limited detail on ECG changes and their clinical significance. 1653 |
| Grafapex (treosulfan) | 214759, 2025-01-21 202 | No formal mean ΔQTc, confidence interval, or exposure-response result was reported. Of 35 evaluable patients with post-baseline ECGs, 2 changed to abnormal ECG (one asymptomatic T-wave negativity; one sick sinus/atrial fibrillation). Nonclinical hERG inhibition was not significant at 1,000 µM. 1800 | Not adequately characterized | A thorough-QT study in healthy volunteers was not feasible because treosulfan is an alkylating agent used as a preparative regimen before allogeneic hematopoietic stem-cell transplantation. FDA therefore required a postmarketing patient study at the recommended dosage to exclude large mean QT/QTc increases (>20 ms), including evaluation of treosulfan and its active metabolite. 1799 | |
| Lynkuet (elinzanetant) | 219469, 2025-10-24 239 | Single oral doses up to 5 times the maximum recommended dose were assessed. 2395 | No clinically relevant prolongation of the QTc interval was observed. 2395 | No clinically relevant prolongation | The QTc effect when elinzanetant is co-administered with strong CYP3A4 inhibitors has not been sufficiently characterized. No rationale for this limitation is stated in the retrieved document. 2395 |
| Zycubo (copper histidinate) | 211241, 2026-01-12 205 | Among 11 patients with available ECGs, two had QTcF >450 ms. FDA and the applicant concluded that no signal for significant abnormalities/QT prolongation was identified, but no mean ΔQTc, 90% confidence interval, or exposure–QTc analysis was reported. In the detailed record review, no subject had QTcF >450 ms after initiation of ZYCUBO; one pre-treatment borderline QTc was 460 ms, and the other patient's intermittent >450-ms readings were associated with concomitant QT-prolonging medications and normalized after those medicines were stopped despite continued copper histidinate. 2301 | No clinically relevant prolongation | A formal thorough-QT study was not needed because copper histidinate is endogenous and treatment is intended to maintain serum copper within the normal physiologic range. FDA had additionally noted that copper intake at recommended CUTX-101 doses does not exceed that from approved copper-containing supplemental diets for infants. Assessment was limited because ECGs were not scheduled in the clinical-study protocols, leaving only 11 patients with available ECGs. 2303 |
Not evaluated / waived (14)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Omlonti (omidenepag isopropyl) | 215092, 2022-09-22 235 | No clinical QT exposure multiple was reported. The nonclinical hERG concentration (10 µM; 4,785 ng/mL) was described as well above clinical plasma concentrations; after 0.0025% once-daily bilateral ocular dosing, omidenepag Cmax was 34.3571–35.5071 pg/mL. 2742 | No human QTc result is available because QT studies and clinical ECG collection were not performed. In nonclinical testing, omidenepag did not inhibit hERG at 10 µM; ECGs in a 13-week topical ocular monkey study showed no treatment-related effects, including QT/QTc evaluation. 2731 | Not adequately characterized | The clinical-pharmacology review concluded that QT-prolongation risk with topical ocular administration appeared low because 10 µmol/L omidenepag had no hERG-current effect and this concentration was well above plasma concentrations detected in the clinical PK study. However, the retrieved rows do not provide a formal FDA waiver/not-required statement or final label section 12.2 wording. 2742 |
| Miebo (perfluorohexyloctane) | 216675, 2023-05-18 188 | No QT exposure multiple was reported. In the phase 2 PK subset after QID dosing for 57 days (n=21), blood concentrations ranged from 0.00 to 25.50 ng/mL (mean 8.192 ng/mL); however, FDA identified bioanalytical issues and stated these PK data could not be used for quantitative PK characterization or labeling. 810 | Unknown | A QT assessment appears not to have been required or reported because perfluorohexyloctane is administered topically to the eye, acts locally, and systemic exposure was expected to be low. FDA further noted that topical ocular drugs are generally not expected to produce high systemic exposure; perfluorohexyloctane is physiologically and chemically inert, and low systemic exposure was observed in rabbit studies. 810 | |
| Posluma (flotufolastat f-18 gallium) | 216023, 2023-05-25 255 | The drug was administered as a single dose in the microdose range; no QT-specific dose or exposure multiple relative to the maximum recommended/high clinical exposure was reported. 734 | Only minor fluctuations in mean QTc change from baseline to safety follow-up were reported. Among patients with ECGs, 25 had QTc change ≤30 ms, 3 had change >30–60 ms, and 1 had change >60 ms with a shift to QTc >500 ms. No treatment-emergent adverse events related to ECG parameters were reported. 734 | Not adequately characterized | A thorough-QT clinical trial was not conducted or considered necessary because flotufolastat F 18 is administered as a single dose in a microdose range. 734 |
| Defencath (heparin sodium; taurolidine) | 214520, 2023-11-15 261 | Not adequately characterized | DEFENCATH is a catheter-lock solution that is instilled after hemodialysis and withdrawn before the next session; it is not intended for systemic administration. The clinical review states that exposure to components is minimal when used as directed, and no thorough-QT or other clinical-pharmacology study was required. 2615 | ||
| Filsuvez (birch triterpenes) | 215064, 2023-12-18 200 | No QT-specific dose or exposure multiple relative to maximum recommended/high clinical exposure was reported. Systemic exposure was limited and variable after topical treatment: 67% of pediatric subjects had venous betulin concentrations below 10 ng/mL on Day 90; highest observed venous concentrations were 33 ng/mL in adults and 207 ng/mL in pediatric subjects. 1203 | Not adequately characterized | The documents state only that QT was not assessed in BEB-13. They also describe limited, difficult systemic PK assessment in epidermolysis bullosa because blood draws can elicit an immune response and worsen disease; FDA considered the limited PK assessment, though not ideal, acceptable. No provided row gives a specific rationale for waiving a standard QT assessment or provides Cardiac Electrophysiology section 12.2 wording. 1203 | |
| Yorvipath (palopegteriparatide) | 216490, 2024-08-09 191 | No formal QTc exposure multiple relative to the maximum recommended or high clinical exposure was reported because a TQT study was waived. The waiver rationale was that active-moiety systemic concentrations were below the sub-nanomolar scale and appeared to be within the normal range of the endogenous moiety. Separately, a maximum single dose of 124 mcg was studied in healthy subjects, versus a recommended starting dose of 18 mcg once daily; these rows do not report a QTc assessment at that dose or an exposure multiple. 1651 | No clinically meaningful ECG abnormalities were observed during palopegteriparatide treatment in healthy subjects or patients with hypoparathyroidism. No mean ΔQTc, 90% confidence-interval upper bound, or quantitative <10-ms result was reported in the provided documents. 1650 | No clinically relevant prolongation | FDA had agreed to waive a TQT study because exposure of the active moiety was far below the sub-nanomolar scale and appeared to fall in the normal range of the endogenous PTH moiety it mimics. FDA also noted that the product is made of naturally occurring amino acids; therefore, a dedicated QTc assessment was not needed. 1649 |
| Aqneursa (levacetylleucine) | 219132, 2024-09-24 129 | No QT-specific dose/exposure multiple was reported. The maximum proposed and maximum clinical-trial dose was 4 g/day (2 g morning, 1 g noon, 1 g evening). At steady state in 17 patients, mean (SD) Cmax was 8.3 (3.3) µg/mL and AUC0–24 was 33.2 (12.5) h·µg/mL. 1525 | No quantitative QTc result (such as mean change or 90% CI upper bound) was reported. The applicant concluded that nonclinical and clinical data showed no potential for QT/QTc prolongation or other cardiovascular findings; FDA agreed. 1525 | No clinically relevant prolongation | A TQT waiver was requested and accepted based on the applicant’s nonclinical and clinical evaluation showing no potential for QT/QTc prolongation and no other cardiovascular-related findings. The pharmacokinetics of NALL had not been assessed in healthy subjects. 1525 |
| Tryptyr (acoltremon) | 217370, 2025-05-28 172 | At the therapeutic regimen (0.003% ophthalmic solution, one drop in each eye twice daily), systemic exposure was negligible: 22 of 25 subjects had no measurable plasma acoltremon (<20 pg/mL), and the few measurable concentrations ranged from 22.8 to 213 pg/mL. No supratherapeutic dose or QT exposure multiple relative to clinical exposure was reported. 1853 | Unknown | The apparent basis for not conducting a standard QT assessment was negligible systemic exposure following topical ocular administration. In COMET-4, only 3 of 25 treated subjects had samples above the 20-pg/mL quantification limit; five of the six detectable samples were baseline or predose, and dietary exposure could not be excluded because acoltremon is a GRAS food additive. 1865 | |
| Vizz (aceclidine hydrochloride) | 218585, 2025-07-31 144 | No supratherapeutic QT assessment or exposure multiple was studied/reported. The highest human dose evaluated was aceclidine hydrochloride 1.75% once daily, the same single dose level studied in phase 2/3; at Day 8, mean surrogate-metabolite exposure was Cmax 2.114 ng/mL and AUC0-t 4.899 hr·ng/mL. 2009 | Not adequately characterized | The stated rationale for not studying QT prolongation was very limited systemic exposure after ocular dosing; aceclidine itself was not measurable in plasma because it is rapidly hydrolyzed in the eye, and the measured metabolite (3-quinuclidinol) was considered pharmacologically inactive at the proposed dosage. 2029 | |
| Kygevvi (doxecitine; doxribtimine) | 219792, 2025-11-03 112 | At the proposed maintenance dose of 800 mg/kg/day, population-PK estimated steady-state geometric-mean Cmax for doxecitine and doxribtimine was within the range of endogenous plasma concentrations reported in healthy humans. No numeric exposure multiple relative to clinical exposure was provided. 2223 | Independent centralized overread of ECGs from TK0102 found no evidence of clinically significant effects on heart-rate-corrected QT (QTc) or other ECG parameters. No mean QTc effect or 90% CI upper bound was provided. 2220 | No clinically relevant prolongation | FDA determined under IND 134073 that a thorough QT/QTc study was not needed because systemic exposures after the proposed oral doses in patients with TK2d were within the range of endogenous doxecitine and doxribtimine concentrations in healthy subjects. 2222 |
| Yuviwel (navepegritide) | 219164, 2026-02-27 127 | TCC-101 evaluated doses up to 150 mcg/kg. The highest predicted free CNP (89-126) concentration in the target pediatric population at 100 mcg/kg once weekly was 72.5 pmol/L, similar to the highest concentration in the concentration-QTc analysis (73.4 pmol/L). 2394 | The concentration–ΔΔQTcF slope was shallow, negative, and not statistically significant. At doses up to 150 mcg/kg, navepegritide had no clinically relevant effect on ECG parameters, including heart rate and PR and QRS intervals; with the proposed regimen, it did not prolong QTc to any clinically relevant extent. 2394 | No clinically relevant prolongation | FDA granted a thorough-QT waiver because navepegritide is a large, targeted protein that would not require a thorough-QT study. 2393 |
| Tauklarify (florquinitau f-18) | 220496, 2026-08-13 97 | The maximum recommended dose is 185 MBq (5 mCi) IV. The highest dose in the QT assessment was 370 MBq (2× the recommended dose), but a high-clinical-exposure scenario was not defined and a Cmax ratio was reported as not applicable. Estimated plasma Cmax after 370 MBq was 0.031 nM; the hERG safety margin was at least approximately 3,210-fold versus the theoretical clinical exposure. 2571 | No formal mean placebo-corrected QTc effect or 90% confidence-bound result was reported. The preliminary concentration–ΔQTcF analysis showed no relationship between ΔQTcF and coincident predicted parent-drug concentrations. In four studies, paired pre/post ECGs were available for 46 participants; 34 (74%) had no noteworthy categorical QTc change. The available ECG data were limited by singlet, non-centrally read ECGs, heterogeneous populations, and no placebo controls. 2572 | No clinically relevant prolongation | The assessment was waived/limited because systemic exposure at the recommended 5-mCi dose was very low (theoretical Cmax <0.269 ng/mL [0.00097 µM]) and the in-vitro hERG margin was large (about 3,210-fold). Earlier FDA feedback had found the prior clinical ECG/PK data inadequate as a TQT substitute because they had not demonstrated sufficiently high exposure or high-quality ECG collection/analysis; FDA had recommended a TQT study if those standards were not met. The later pre-NDA determination accepted no additional QT study based on the low exposure and hERG margin. 2573 |
| Zanvastro (zilganersen) | 220210, 2026-09-03 276 | Zilganersen is not expected to affect the QTc interval; no numerical QTc effect or confidence interval is reported. 2607 | No clinically relevant prolongation | Assessment was limited/waived based on the chemical properties of zilganersen and absence of cardiac electrophysiology findings in nonclinical studies. 2607 | |
| Etcamah (camizestrant) | 220359, 2026-09-04 275 | The approved dose is 75 mg once daily. The planned postmarketing QTc trial will study 75 mg and 150 mg once daily (150 mg = 2 times the approved dose). The label reports that camizestrant exposure increases more than dose-proportionally over 25-450 mg once daily (0.3-6 times the approved dose), and that coadministration with ribociclib increases steady-state AUC and Cmax approximately 2-fold; however, no QTc effect estimate at these exposures is provided. 2603 | No numerical mean QTc change or confidence-interval bound is reported. Label: "There is insufficient information to fully characterize the effect size of camizestrant on the QTc interval." Clinically, QTc interval prolongation occurred in 2.6% of patients receiving camizestrant plus a CDK4/6 inhibitor in SERENA-6; one case of Torsades de Pointes occurred in a dose-finding trial with camizestrant plus ribociclib. 2603 | Not adequately characterized | No rationale for omitting or limiting a standard preapproval QT assessment is stated in the provided documents. FDA instead imposed a postmarketing requirement because camizestrant has a known serious risk of QTc prolongation and stated that only a clinical trial would be sufficient to assess this risk. 2596 |
Not found in retrieved documents (3)
| Drug (ingredient) | NDA / approval | Exposure coverage | QTc result | Outcome | Rationale or limitation |
|---|---|---|---|---|---|
| Izervay (avacincaptad pegol sodium) | 217225, 2023-08-04 175 | Nonclinical doses were 10, 30, and 100 mg/kg IV in monkeys; the excerpt reports testing at 100 µM in the ion-channel assay. It does not provide a comparison with the maximum recommended dose or high clinical exposure. 1235 | The excerpt states that an IC50 was not determined but was considered >100 µM, supporting minimal risk for QTc prolongation. It does not report a human mean QTc effect or 90% confidence-interval upper bound. 1235 | Unknown | |
| Iomervu (iomeprol) | 216017, 2024-11-27 195 | Unknown | |||
| Pixclara (floretyrosine f 18) | 218592, 2026-09-11 278 | Unknown |
Caveats
- Classification was extracted by reading retrieved pages per application; a few records (for example Iomervu, Pixclara, Izervay, Miebo) had no QT-specific text retrieved, which reflects a retrieval gap rather than proof that no assessment exists.
- Where a review and the final label differ in emphasis, the table reports what the retrieved documents state; check the current label before relying on exact wording.
- Therapeutic protein and antibody BLAs are outside this table.
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