Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Abstract

N‐Nitrosamine (NA) impurities are considered genotoxic and have gained attention due to the recall of several marketed drug products associated with higher‐than‐permitted limits of these impurities. Rifampicin is an index inducer of multiple cytochrome P450s (CYPs) including CYP2B6, 2C8, 2C9, 2C19, and 3A4/5 and an inhibitor of OATP1B transporters (single dose). Hence, rifampicin is used extensively in clinical studies to assess drug–drug interactions (DDIs). Despite NA impurities being reported in rifampicin and rifapentine above the acceptable limits, these critical anti‐infective drugs are available for therapeutic use considering their benefit–risk profile. Reports of NA impurities in rifampicin products have created uncertainty around using rifampicin in clinical DDI studies, especially in healthy volunteers. Hence, a systematic investigation through a literature search was performed to determine possible alternative index inducer(s) to rifampicin. The available strong CYP3A inducers were selected from the University of Washington DDI Database and their in vivo DDI potential assessed using the data from clinical DDI studies with sensitive CYP3A substrates. To propose potential alternative CYP3A inducers, factors including lack of genotoxic potential, adequate safety, feasibility of multiple dose administration to healthy volunteers, and robust in vivo evidence of induction of CYP3A were considered. Based on the qualifying criteria, carbamazepine, phenytoin, and lumacaftor were identified to be the most promising alternatives to rifampicin for conducting CYP3A induction DDI studies. Strengths and limitations of the proposed alternative CYP3A inducers, the magnitude of in vivo CYP3A induction, appropriate study designs for each alternative inducer, and future perspectives are presented in this paper.

PBPK perspective on alternative CYP3A4 inducers for rifampin

“…(Figure 1a ). This suggests that carbamazepine and phenytoin are the primary and secondary alternatives for rifampin, in agreement with a recent systemic review by Bolleddula et al 5 based on DDI clinical studies. Lumacaftor, considered a potential alternative in the review, is not included in the analysis here due to insufficient published data for DDI verification.…”

Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions

“…56 This is demonstrated by the induced exposure ranges observed with carbamazepine, which has varying induction regimens, and may be a future concern if rifampicin is no longer used for induction assessments. 66 Presently, 47 clinical OC-DDI studies were modeled and noted considerable variable historical clinical designs from just single dose to steady-state, to full crossover multi-cycle assessment. The commentaries by Lesko (2018) and Sun et al (2020) call for consistent integrative analysis searching beyond PBPK and use of pharmacodynamic (PD) biomarkers.…”

“…Furthermore, there are limited clinical data appropriately reported with other known clinical inducers (e.g., rifabutin, carbamazepine, or phenytoin) and observed greater variability 56 . This is demonstrated by the induced exposure ranges observed with carbamazepine, which has varying induction regimens, and may be a future concern if rifampicin is no longer used for induction assessments 66 …”

“… 56 This is demonstrated by the induced exposure ranges observed with carbamazepine, which has varying induction regimens, and may be a future concern if rifampicin is no longer used for induction assessments. 66 …”

Tiered approach to evaluate the CYP3A victim and perpetrator drug–drug interaction potential for vonoprazan using PBPK modeling and clinical data to inform labeling

“…No difference was observed in the PKs of amoxicillin but the clarithromycin exposure increased by 1.5‐fold when administered as triple therapy. A clinical study evaluating the impact of a strong CYP3A inducer, rifampin, on vonoprazan exposure was paused due to potential safety issues related to possible nitrosamine contaminants in rifampin clinical supplies 16,17 . Although other strong CYP3A inducers, including phenytoin or carbamazepine, were considered as an alternative to rifampin for the clinical DDI study, a modeling approach was instead chosen to avert potential safety concerns when these agents are administered to healthy participants 18–20 …”