The Need for Multiple Doses of 400 mg Ketoconazole as a Precipitant Inhibitor of a CYP3A Substrate in an In Vivo Drug‐Drug Interaction Study

A Food and Drug Administration (FDA) guidance document has recommended that “when using ketoconazole (KTZ) as an inhibitor of CYP3A, dosing at 400 mg q.d. for multiple days would be preferable to lower doses.”1 Ketoconazole dosed for 3 days or longer prior to concomitant administration of a cytochrome P3A4/5 (CYP3A) recipient substrate is emerging as a common practice in drug interaction studies. However, despite numerous inferences, we do not find convincing evidence that a single 400-mg KTZ dose is insufficient to elucidate clear inhibition of a CYP3A substrate. We propose that a single 400-mg KTZ dose should be considered as a practical alternative, as the ensuing interaction study would be less expensive and complex. Ketoconazole is the recommended inhibitor for evaluating an in vivo drug-drug interaction potential of a new molecular entity that is primarily metabolized by CYP3A isoenzymes. It fulfills the criteria as a suitable probe because it is a highly potent CYP3A inhibitor with Ki values generally in the nanomolar range.2 A daily dose of 400 mg KTZ represents the maximum and safe therapeutic dose and could completely inhibit CYP3A isoenzymes in vivo.3 Unlike some other inhibitors, KTZ is recognized as a competitive and reversible CYP3A inhibitor.4 CYP3A inhibition could be largely dependent on whether there is a sufficient concentration margin between the precipitant KTZ and the recipient CYP3A substrate, and the interaction could be time dependent. Ketoconazole has a terminal half-life of about 3 to 5 hours, and the peak concentration (mean of 7–11 μg/mL) is achieved at about 2 hours.5,6 There will be minimum KTZ accumulation and thus no anticipated increase in CYP3A inhibition following multiple daily doses of KTZ. For a single 400-mg KTZ dose, sufficient KTZ concentrations (estimated mean of 1–3 μg/mL)5,6 could remain at 12 hours after dosing to inhibit CYP3A isoenzymes. This phenomenon is illustrated by a KTZ interaction study with budesonide, where a 4-fold increase in budesonide AUC was reported when KTZ (200 mg qd for 4 days) was dosed 12 hours apart from budesonide dosing, whereas a corresponding 7-fold increase occurred when both drugs were dosed concomitantly.7 Chien et al8 predicted a 25% increase in the plasma AUC of midazolam (MDZ, a sensitive CYP3A substrate) when concomitantly administered with multiple 400-mg daily doses of KTZ, as compared with the interaction with a single 400-mg KTZ dose. This deduction has been confirmed in a recent MDZ-KTZ interaction study, where a 36% higher MDZ AUC on day 5 over day 1 was reported.9 However, both 1-day and 5-day concomitant MDZ-KTZ regimens produced clear increases in MDZ AUC when compared with the AUC for the MDZ-alone regimen (10.3- and 14.0-fold, respectively). These findings further support the view that an increase in inhibition following multiple KTZ doses, if present, could be regarded as clinically predictable from a study using a single 400-mg KTZ dose.