Drug Interaction Studies With CYP3A Substrates: How Much Inhibitor Pre‐exposure Is Needed?

Pharmaceutical sponsors developing drug candidates that are partly or entirely cleared via metabolism by CYP3A enzymes inevitably face the scientific and clinical question of the extent to which coadministration of another medication that inhibits CYP3A activity (a “perpetrator”) alters the pharmacokinetics and pharmacodynamics of the candidate drug under study (the “victim”). The general crossover design of clinical drug-drug interaction (DDI) studies to address this question is accepted by the scientific and regulatory communities. Likewise, the choice of perpetrator drugs is noncontroversial. To create a “worst-case scenario,” sponsors may choose the perpetrator from among the most potent CYP3A inhibitors, such as ketoconazole, ritonavir, or itraconazole. If delineating the effect of “moderate” CYP3A inhibition is an objective, then a perpetrator such as erythromycin or clarithromycin could be chosen. What does remain controversial is the duration of preexposure to the inhibitory perpetrator necessary to ensure that the observed DDI does in fact represent the worst case—that is, the maximum extent of inhibition (increase in area under the plasma concentration curve [AUC] for the victim drug) that the perpetrator can produce. In purely scientific terms, extended pre-exposure to the perpetrator makes sense. This ensures that systemic exposure to the inhibitor will be at steady-state at the time the victim is given, and that the inhibitor’s effect of the metabolic enzyme is (presumably) maximal. However there is a downside to extended pre-exposure to the perpetrator. There is risk—low and acceptable, but still nonzero—to volunteer participants in the study, and there is an economic cost to the sponsor as well. Each day of study duration has a dollar cost which adds to the net cost of drug development. On balance, we should be designing DDI studies with a perpetrator pre-exposure duration that is the minimum necessary to achieve the scientific objectives. Until recently, these minimum pre-exposure durations have not been established. Ketoconazole is the single most widely used “strong” CYP3A inhibitor applied in DDI studies, and the usual convention has been 4 to 7 days of pre-exposure to ketoconazole prior to challenge with the drug candidate being tested as the victim. Going back to the 1990s, we noted that inhibition of triazolam clearance by ketoconazole was similar whether ketoconazole pre-exposure was 18 hours or 4 days. The issue was settled in a systematic study by Stoch and associates, demonstrating that inhibition of oral midazolam clearance by ketoconazole was 75% maximal if midazolam was given without pre-exposure, concurrently with the dose of midazolam. With 24 hours of ketoconazole pre-exposure, inhibition was essentially identical to 4 days of pre-exposure (Figure 1). The findings are fully consistent with the pharmacokinetic properties of ketoconazole and its reversible mechanism of CYP3A inhibition. If erythromycin is used as a “moderate” CYP3A inhibitor in a DDI study, the situation is different because erythromycin is a mechanism-based (irreversible) inhibitor. Okudaira et al showed that inhibition of midazolam clearance was 70% maximal with 48 hours of pre-exposure to erythromycin (Figure 2). Inhibition with 5 and 8 days of erythromycin pre-exposure were not distinguishable. Based on the solid scientific data as described, industrial scientists constructing DDI study protocols involving CYP3A inhibitors should have additional tools to 448745 CPD1310.1177/2160763X12448745Greenbl attClinical Pharmacology in Drug Development 2012© The Author(s) 2012