123: Assessment of Impact of CYP3A4 Inducers on Investigational Drugs Informed By Clinical Drug-Drug Interaction Data: A Survey of Drugs Approved By FDA

Drug-drug interaction (DDI) are a concern with polypharmacy. Co-administration of drugs that are inducers of metabolic enzymes and/or drug transporters can decrease the concentrations of co-medicants leading to reduced efficacy. Thus, it is critical to characterize the impact of inducers on the pharmacokinetics of investigational drugs during development to better inform health care providers on the risk of DDI.  Historically, clinical induction based DDI for CYP3A4 substrates was conducted using rifampin, a prototype inducer, however its use is currently precluded due to unresolved nitrosamine impurities which pose a potential carcinogenesis risk. Alternative strong inducers, including carbamazepine and phenytoin, have been proposed in the interim. However, there remain concerns with administering these to healthy subjects due to adverse events.  Evaluation of new approaches is desired due to the challenge to apply the traditional paradigm.

Description of Methods & Materials:

A survey was conducted to look through the prescriber information (product labeling) of new molecular entities (NMEs) approved by US Food and Drug Administration (FDA) from 2012 to 2022. Clinical DDI study results reflected by the change of AUC of NMEs (as substrates) were collected for those NMEs that are CYP3A4 substrates and had studies conducted with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) and with strong or moderate inducers of CYP3A4. The labeling recommendations in terms of using those NMEs with CYP3A4 inducers were also gathered.

Data & Results:

In total, 107 drugs are included in our dataset. Rifampin was used as the strong CYP3A4 inducer in most studies. Half of these (n=53) had AUC increased at least 2-fold (AUCR, AUC ratio) by strong inhibitors of CYP3A4, indicating CYP3A4 plays a major role in their elimination in vivo (Table 1). Almost all of these (n=51) had AUC decreased by half or more (AUCR ≤0.5) in the presence of strong CYP3A4 inducers, with majority of them had AUC reduced by 3-fold or more (AUCR≤0.33) (Table 2). For the rest half (n=54), CYP3A4 plays a less role in their clearance, with AUCR < 2 in the presence of strong CYP3A4 inhibitors. However, strong CYP3A inducers still showed large impact, with about 80% of those (n=42) having AUC decreased by half or more (AUCR ≤0.5) and close to 50% of those having AUC reduced by 3-fold or more (AUCR ≤0.33). These results led to labelings that recommend avoiding concomitant uses with strong inducers of CYP3A4 for more than 80% of these 107 drugs.

Interpretation, Conclusion or Significance:

The results demonstrated that the impact of strong CYP3A4 inducers is generally larger than that of strong CYP3A4 inhibitors. For an investigational drug mainly metabolized by CYP3A4 in vitro, a clinical DDI study is often conducted with a strong CYP3A4 inhibitor. If the major role of CYP3A4 is confirmed in vivo (e.g., AUCR ≥2), it can be anticipated that strong CYP3A inducers greatly reduce the drug’s exposure and often cause clinically significant interactions. The results support recommendation in the ICH M12 guideline that, if it is expected that co-administration with strong inducers should be avoided, a moderate inducer may be used in the clinical study evaluating the impact of inducers.

Disclosures:

The views expressed in this abstract are those of the authors. No official support or endorsement by the United States Food and Drug Administration (USFDA) is provided or should be inferred.

Citations/References:

1. Bolleddula J, et al. Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug-drug interaction studies. Clin Transl Sci. 2022 Sep;15(9):2075-2095.

2. International Council for Harmonisation. ICH Harmonised Guideline – Drug Interaction Studies M12 (Draft version). https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-guideline-m12-drug-interaction-studies-step-2b_en.pdf (2022).

Additional Information/Authors: N/A