FDA Requirements for CYP3A and Transporter Drug Interaction Studies and Labeling in Recent NDA Clinical Pharmacology Reviews

How FDA evaluates CYP3A and transporter drug interactions in recent NDA clinical pharmacology reviews

FDA clinical pharmacology reviewers follow a consistent sequence for new molecular entities. First, they expect clinical studies with a strong CYP3A index inhibitor and a strong inducer when the drug is a CYP3A substrate. PBPK modeling then extends those results to moderate inhibitors and inducers, but only when reviewers judge the model adequately verified. Perpetrator risk is assessed with midazolam and, where in vitro inhibition exceeds the M12 cutoff for a transporter, with clinical probe-substrate studies. Where the data are incomplete, reviewers fill the gap with labeling (avoid, reduce dose, monitor, or contraindicate) and with postmarketing requirements (PMRs) or commitments (PMCs). The sections below describe the framework reviewers apply and show how it played out across recent original NDAs.

The framework reviewers apply

ICH M12 sets the study expectations. FDA's final M12 Drug Interaction Studies guidance (August 2024) recommends that when an investigational drug is a CYP3A substrate, the first clinical DDI studies test a strong index inhibitor and a strong index inducer ⁴⁴³. Clarithromycin and itraconazole are listed as strong CYP3A index inhibitors. Carbamazepine, phenytoin and rifampin are listed as strong inducers, and efavirenz as a moderate inducer ⁴⁴⁴⁴⁴⁵. A negative result with a strong index inhibitor can generally be extrapolated to strong, moderate and weak CYP3A4 inhibitors. Mechanistic modeling can in some cases extrapolate a positive finding to moderate and weak inhibitors ⁴⁴⁸. When a drug both inhibits and induces CYP3A, M12 recommends evaluating substrate pharmacokinetics at early and late time points ⁴⁴⁷.

Transporters follow in vitro cutoffs and clinical follow-up. M12 recommends in vitro inhibition testing against P-gp, BCRP, OATP1B1/1B3, OAT1/3, OCT2 and MATE1/MATE2-K ⁴¹⁸⁴¹⁹. It sets the following basic cutoffs for ruling out inhibition risk ⁴²¹⁴²²⁴²³⁴²⁴⁴²⁵⁴²⁶:

Transporter	In vitro cutoff to exclude inhibition risk
P-gp/BCRP (oral drug)	(dose/250 mL)/IC50 < 10 ⁴²²
P-gp/BCRP (parenteral drug or metabolite)	Cmax,u/IC50,u < 0.02 ⁴²³
OATP1B1/1B3	Cmax,inlet,u/IC50,u < 0.1 ⁴²⁴
OAT1/OAT3/OCT2	Cmax,u/IC50,u < 0.1 ⁴²⁵
MATE1/MATE2-K	Cmax,u/IC50,u < 0.02 ⁴²⁶

Positive signals may lead to a clinical study, depending on co-medication likelihood and the safety profile of the substrates. Mechanistic static models, PBPK or endogenous biomarkers are acceptable alternatives when their validity is supported ⁴²⁸. M12's example clinical substrates are dabigatran etexilate, digoxin and fexofenadine for P-gp ⁴³¹, rosuvastatin and sulfasalazine for BCRP ⁴³², statins and bosentan for OATP1B ⁴³³, furosemide and others for OAT1/3 ⁴³⁴, and metformin for OCT2/MATE ⁴³⁵. FDA notes that no true index substrates exist for transporters ⁴³⁶. Plasma coproporphyrin I (CPI) is recognized as an OATP1B1/3 biomarker. A postdose-to-baseline CPI Cmax and AUC ratio below 1.25 indicates low likelihood of a clinical OATP1B DDI ⁵²²⁵²³. Cocktail studies are acceptable when the probes are specific and do not interact with one another ⁵²⁴.

Labeling placement follows the 2024 draft DDI labeling guidance. The draft Drug Interaction Information in Human Prescription Drug and Biological Product Labeling (October 2024) assigns content as follows ¹⁹⁴¹⁹⁵:

Section 2 carries specific dose modifications for the subject drug ¹⁸⁷.
Section 4 lists combinations whose risk clearly outweighs benefit ¹⁹⁷.
Section 5 covers clinically significant hazards ¹⁹⁸.
Section 7 leads with practical prevention and management instructions ¹⁹⁹²⁰⁰.
Section 12.3 holds positive and pertinent negative study results, without management instructions ¹⁷⁵.

Separately, the 2023 Clinical Drug Interaction Studies With Combined Oral Contraceptives guidance expects COC interaction potential to be evaluated and communicated in labeling ⁵²⁵. It calls for a COC study for teratogenic drugs even when a CYP3A probe suggests weak or no induction ⁵²⁶.

CYP3A victim interactions: strong inhibitor and inducer studies drive labeling

Across recent reviews, itraconazole and rifampin studies were the standard evidence base. The magnitude of the exposure change mapped fairly predictably to the labeling outcome.

Drug	Key clinical finding	Labeling or review outcome
Pyrukynd (mitapivat)	Itraconazole raised AUC 4.9-fold; rifampin lowered AUC 91% ⁶⁸	Avoid strong CYP3A inhibitors and inducers ⁶⁸⁴². With moderate inhibitors, monitor and cap the dose at 20 mg BID ²⁶²²⁴⁸
Truqap (capivasertib)	Itraconazole raised AUC 1.95-fold; FDA analysis showed efavirenz lowered AUC 60% ⁸¹⁸²	Avoid strong inhibitors and moderate/strong inducers. Reduce to 320 mg BID with moderate inhibitors or an unavoidable strong inhibitor ⁸⁰⁴⁸
Exkivity (mobocertinib)	Itraconazole raised combined molar AUC 6.27-fold; rifampin lowered it about 95% ⁹¹	Avoid strong and moderate inhibitors and inducers. Reduce the dose about 50% with ECG monitoring if a moderate inhibitor is unavoidable ⁹¹⁹⁴⁵⁴
Ibtrozi (taletrectinib)	Itraconazole raised AUC 3.3-fold; rifampin lowered AUC 86% ⁸⁵	Avoid strong and moderate CYP3A4 inhibitors and inducers ⁸⁷⁵²
Ogsiveo (nirogacestat)	Itraconazole raised single-dose AUC 8.2-fold ⁹⁸	FDA revised labeling to avoid strong or moderate CYP3A4 inhibitors and inducers ¹⁰³¹⁰⁴⁵⁶
Beqalzi (sonrotoclax)	Posaconazole raised AUC up to 16-fold; itraconazole 11-fold ¹⁰⁹	20 mg daily target with strong inhibitors, which are avoided during ramp-up. Avoid strong or moderate inducers ¹¹⁰¹¹¹⁵⁸
Zenbexus (iberdomide)	Itraconazole raised AUC about 2.4-fold ⁷⁵	Avoid strong inhibitors or reduce the dose. Lower starting dose with moderate inhibitors ⁷⁸⁷⁷⁴⁵
Jascayd (nerandomilast)	Itraconazole raised AUC 2.2-fold ⁶⁴	Halve the dose (18 to 9 mg BID) with strong CYP3A4 inhibitors. Avoid moderate or strong inducers ⁶¹⁶⁶⁴¹
Joenja (leniolisib)	Itraconazole raised AUC about 2-fold; quinidine had no effect ⁸⁹	Avoid strong CYP3A inhibitors. No adjustment for P-gp or weak/moderate inhibitors ⁸⁹⁵³
Journavx (suzetrigine)	Itraconazole raised AUC 4.79-fold; rifampin lowered AUC 93% ³⁵²³⁵³	Strong inhibitors contraindicated. Reduce the dose with moderate inhibitors. Avoid strong or moderate inducers ³⁵³³⁵⁵³³⁴
Litfulo (ritlecitinib)	Rifampin lowered AUC about 44% ²⁶³	Avoid strong CYP3A inducers because of potential loss of efficacy ²⁶⁴²⁴⁴
Lazcluze (lazertinib)	Rifampin lowered AUC to 16% of control ²⁵⁸	Review recommended avoiding moderate CYP3A4 inducers as well ²⁵⁹²⁴²
Oxbryta (voxelotor)	Itraconazole raised exposure only about 10% ⁷⁰	No inhibitor adjustment. Higher doses specified for unavoidable strong or moderate inducers ⁷⁰⁴³

Exkivity, Truseltiq, Ukoniq and Oxbryta have since been withdrawn from the US market; their rows show how reviewers handled the interaction data at approval, not current labeling.

Two patterns stand out. First, contraindications are reserved for the largest effects or for combinations with serious safety consequences. Exxua carries a contraindication for strong CYP3A4 inhibitors, which raise its exposure about 5-fold, and a dose reduction for moderate inhibitors (about 2.6-fold) ⁵⁰⁹. Myqorzo (aficamten) contraindicates rifampin; PBPK predicted a 79% AUC decrease ²⁵³²⁵⁴²³⁷. Second, induction findings are interpreted mechanistically. For Vanrafia (atrasentan), rifampin's concurrent OATP1B inhibition masked CYP3A induction, so AUC was unchanged even though trough concentrations fell by more than 80%. Reviewers still supported avoiding strong or moderate inducers ²⁶⁵²⁶⁶²⁴⁷. For Brenzavvy (bexagliflozin), the reviewer cautioned that a three-day rifampin pretreatment might not capture maximal induction ²⁶⁷²⁴⁹.

PBPK for moderate inhibitors and inducers: accepted only when verified

Reviewers routinely accept PBPK to extrapolate clinical strong-perpetrator results to moderate perpetrators. Accepted examples include:

Mobocertinib: about 2-fold AUC with moderate inhibitors and about 60% lower exposure with efavirenz ⁹¹⁹³
Taletrectinib: up to 2.6-fold AUC with moderate inhibitors ⁸⁶
Suzetrigine: 3.0-fold AUC with fluconazole, which supported a reduced regimen ²⁵¹
Rilzabrutinib: about 70% lower AUC with efavirenz ²⁵⁵
Lazertinib: at least 44% lower AUC with efavirenz ²⁵⁸²⁴⁵

Reviewers also reject or limit models that are not adequately verified:

Sohonos (palovarotene): the model was not considered adequate for predicting most CYP inhibitor or inducer effects ²⁹¹²⁷⁴.
Quviviq (daridorexant): the model was verified against diltiazem and efavirenz but could not accurately predict the magnitude of strong-modulator effects ²⁹⁷²⁷⁷.
Wayrilz (rilzabrutinib): the victim model's efavirenz extrapolation was accepted (above), but the reviewer found the cimetidine and dexamethasone perpetrator models inadequately verified ³⁴⁸³⁴⁹³²⁵. Transporter-substrate predictions were considered inadequate ³²¹²⁸⁸.
Filspari (sparsentan) and Truqap: reviewers flagged that rifampin models omitting P-gp (and, for capivasertib, UGT2B7) induction may underpredict the decrease in exposure ²⁹⁹²⁸⁵²⁷²²⁵².

When modeling cannot resolve the question, FDA converts the gap into a PMR. Examples:

Truseltiq (infigratinib): itraconazole raised exposure sevenfold, but the moderate-inhibitor effect was uncertain, so FDA required a moderate-inhibitor study ¹⁶⁵¹⁶⁶¹³⁵.
Vonjo (pacritinib): FDA required a revised, validated PBPK analysis, with a clinical study as backup if results are inconclusive ¹⁴⁹¹¹⁹.
Jideytro (zidesamtinib): nonlinear PK made moderate-inhibitor effects unclear. FDA proposed excluding moderate CYP3A inhibitors in labeling and a PMR allowing either a clinical trial or PBPK ¹⁴⁰¹⁴²¹¹⁵.

CYP3A perpetrator effects: midazolam, induction and contraceptives

Midazolam remains the standard probe for perpetrator assessment. Labeling scales with the observed effect:

Drug	Effect on CYP3A substrates	Labeling or review outcome
Paxlovid (nirmatrelvir/ritonavir)	Midazolam AUC ratio 14.3 ⁴⁹⁶	Oral midazolam contraindicated, along with other CYP3A-dependent drugs ⁴⁹⁶⁴⁹⁵⁴⁵⁹
Sunlenca (lenacapavir)	Midazolam AUC increased 3.59-fold ⁴⁰²	Avoid CYP3A substrates for which small concentration changes may cause serious toxicity ⁴⁰⁴³⁸⁸
Scemblix (asciminib)	Midazolam AUC ratio 1.36 at 40 mg BID; 88% increase predicted at 200 mg BID ³⁵⁷³⁵⁸	Monitor at 80 mg/day. At 200 mg BID, avoid narrow-margin substrates or reduce their dose ³⁵⁷³²⁷
Rhapsido (remibrutinib)	PBPK predicted about a 20% to 25% AUC increase at the 25 mg BID dose ³⁷³	Sensitive CYP3A substrates and the evaluated COCs may be coadministered ³⁷⁴³³³
Journavx (suzetrigine), inducer	Midazolam AUC lowered about 48% ³⁵⁰	Avoid CYP3A substrates for which small concentration changes could cause loss of efficacy ³⁵⁴³³⁴
Pyrukynd (mitapivat), inducer	Midazolam AUC lowered 21% to 57% across doses ³⁶⁵	Monitor narrow-therapeutic-index CYP3A substrates. Advise nonhormonal or additional barrier contraception ³⁶⁷⁵⁰⁸

Induction is the area where reviewers most often treat sponsor predictions with skepticism:

Voranigo (vorasidenib): the sponsor's PBPK predicted an 80% or greater decrease in midazolam AUC. FDA considered that estimate potentially excessive, classed vorasidenib as a possible weak-to-moderate inducer, and identified a postmarketing study to determine the magnitude ³⁶¹³²⁸.
Itovebi (inavolisib): FDA could not rule out induction from PBPK ³³⁹³⁴⁰³³⁵ and obtained a PMC for a clinical study with a sensitive CYP3A substrate ¹³⁷¹¹².
Joenja (leniolisib): the induction model could not predict the magnitude of the effect, so FDA required a cocktail DDI study that includes midazolam ³⁸³⁹³¹.

Negative midazolam studies have resolved in vitro signals:

Vanrafia showed in vitro time-dependent inhibition and induction, but midazolam AUC and Cmax ratios were 1.10 and 1.09 ³⁶⁹³³².
Bylvay showed an in vitro intestinal CYP3A inhibition signal, but no inhibition in vivo ⁴⁶⁶⁴⁵⁰.

Transporter interactions: probe-substrate studies and biomarkers

P-gp. Digoxin and dabigatran studies drove monitoring language rather than contraindications:

Xolremdi (mavorixafor) raised digoxin AUC 1.65-fold. The review recommended monitoring narrow-margin P-gp substrates and serum digoxin concentrations ³²¹⁸.
Cibinqo (abrocitinib) raised dabigatran AUC 1.53-fold. No dabigatran adjustment was required, but monitoring or titration was recommended for sensitive P-gp substrates ³⁹⁹³⁸¹.
Paxlovid raised dabigatran AUC 1.94-fold. Labeling recommends dose reduction or avoidance depending on indication and renal function ⁴⁹⁶⁴⁵⁹.

BCRP and OATP1B. Rosuvastatin is the workhorse probe:

Rezdiffra (resmetirom) raised rosuvastatin AUC 1.8-fold and also increased exposure to other statins. FDA set statin dose caps: simvastatin and rosuvastatin 20 mg/day, atorvastatin and pravastatin 40 mg/day ²²²²²³²¹⁰.
Hernexeos (zongertinib) raised rosuvastatin AUC 2.30-fold. Coadministration with sensitive BCRP substrates is not recommended. CPI data argued against relevant OATP1B inhibition, so no adjustment is needed for OATP1B substrates ³³³⁴²⁷.
Rhapsido raised rosuvastatin AUC 1.65-fold, and labeling recommends monitoring with narrow-margin BCRP substrates ²²⁹²³⁰²¹². Its unchanged CPI supported no OATP1B1 inhibition ⁴⁷⁶⁴⁵³.
Fabhalta (iptacopan) had no significant effect on digoxin or rosuvastatin. P-gp, BCRP and OATP1B substrates may be coadministered ²³⁴²³⁵²¹⁸.

Renal transporters.

Cosela (trilaciclib) raised metformin AUC 1.65-fold and cut its renal clearance 37%. FDA found no dose modification warranted because trilaciclib is dosed intermittently ³⁵³⁶²⁸.
Vafseo (vadadustat) roughly doubled furosemide exposure through probable OAT3 inhibition. Reviewers added that labeling should note the potential need for dose adjustment ³⁹⁵³⁹⁷³⁸⁰.
Blujepa (gepotidacin) showed no MATE1/2-K interaction with cimetidine ⁹⁶⁵⁵.

Transporter PMRs are common when in vitro signals exceed cutoffs and no clinical data exist:

Rezurock (belumosudil): clinical study of sensitive P-gp/BCRP/OATP1B1 substrates ¹⁵⁹¹²⁶
Jideytro: required P-gp/BCRP substrate trial ¹⁴²¹⁴³¹¹⁵
Augtyro (repotrectinib): transporter-substrate trials ¹⁴⁷¹¹⁸
Ibtrozi: clinical study of sensitive CYP3A and transporter substrates ¹⁶⁰¹²⁷
Avmapki Fakzynja: MATE2-K substrate or endogenous biomarker evaluation ¹⁵⁶¹²³
Joenja: cocktail study with rosuvastatin and metformin ⁴⁰³¹
Lupkynis (voclosporin): PMC for an OATP1B1 substrate study ¹⁵⁸¹²⁵
Ojemda (tovorafenib): interim labeling to avoid sensitive CYP3A substrates and hormonal contraceptives, with PMRs for enzyme and BCRP substrate studies ¹³⁸¹¹³

Postmarketing requirements and commitments as a bridging tool

Recent approvals show FDA accepting an approval with DDI gaps when labeling provides interim protection. In those cases FDA obtains a PMR or PMC to generate the missing data:

Inducer studies: Jascayd (moderate and strong) ¹⁴⁴¹¹⁶, Hernexeos (moderate) ¹⁶⁴¹³¹, Ensacove (strong) ¹⁵⁷¹³⁰, Ukoniq (strong) ¹⁶¹¹³⁴, and Vanflyta (weak, with the active metabolite) ¹⁶⁷¹³⁶
Bidirectional CYP3A studies: Rezlidhia ¹³⁹¹¹⁴
Combined CYP3A/P-gp questions: Tepmetko received an itraconazole PMR and a rifampin PMC. Interim labeling avoids strong CYP3A4 inducers and dual strong CYP3A/P-gp inhibitors ¹⁵¹¹⁵²¹⁵³¹²⁰

Practical implications for sponsors

Plan itraconazole (or clarithromycin) and rifampin studies early. Reviewers expect these clinical anchors, and labeling recommendations for strong perpetrators rarely rest on modeling alone ⁴⁴³⁴⁴⁴.
Verify PBPK models against clinical moderate-perpetrator data where possible. Account for P-gp and UGT induction by rifampin. Unverified models lead to PMRs or conservative avoidance language ²⁹⁷²⁹⁹¹⁴⁹.
For perpetrator risk, characterize induction clinically. Reviewers discount PBPK-only induction predictions and may require clinical substrate studies after approval ³⁶¹³³⁹³⁸.
Use CPI and cocktail designs to resolve OATP1B and multi-transporter signals efficiently. FDA has accepted CPI data to remove OATP1B labeling concerns ⁵²³³³⁴⁷⁶.
Address hormonal contraceptives explicitly for CYP3A inducers, consistent with the 2023 COC guidance ⁵²⁵³⁶⁷.
Draft Sections 2, 4, 5, 7 and 12.3 consistently with the 2024 draft DDI labeling guidance. Put management instructions in Section 7 and study data in Section 12.3 ¹⁹⁹¹⁷⁵.