Guidance for Rifampin and Midazolam Dosing Protocols To Study Intestinal and Hepatic Cytochrome P450 (CYP) 3A4 Induction and De-induction.

Abstract

Cytochrome P450 3A4 (CYP3A4) catalyses the metabolism of > 30% of clinically used small molecule drugs. Induction of CYP3A4 is often associated with clinically important metabolic drug-drug interactions (DDIs). To collate published data regarding induction of CYP3A4 expression by rifampin and identify an optimal protocol to study DDIs using physiologically based pharmacokinetic (PBPK) modelling. The University of Washington Drug Interaction Database was searched for published data regarding induction of CYP3A4 by rifampin. A verified PBPK model was used to define the optimal dose, duration, timing and route of administration of rifampin and midazolam to assess induction of intestinal and hepatic CYP3A4 by rifampin. Sensitivity analysis was performed to evaluate the impact of participant characteristics including sex, race and age. The maximal induction of intestinal CYP3A4 (9.5-fold) was almost double that of hepatic CYP3A4 (5.5-fold). Maximal induction of intestinal and hepatic CYP3A4 was achieved in > 90% of participants within 5 and 10days, respectively. Intestinal CYP3A4 expression returned to baseline in > 90% of participants within 7days of rifampin cessation, whereas induction of hepatic CYP3A4 persisted for greater than 7days in > 50% of participants. There was a significant difference in magnitude, but not time course, of CYP3A4 induction between males and females. Age and race did not significantly affect either the magnitude or time course of CYP3A4 induction. Maximal induction of intestinal CYP3A4 is achieved faster than hepatic CYP3A4. To assess maximal hepatic CYP3A4 induction, oral rifampin (600mg daily) should be dosed for > 10days.