OIV-B-4Physiologically-based pharmacokinetic models for the inhibition of midazolam clearance by erythromycin and diltiazem

Abstract

BACKGROUND The prediction of the extent of drug-drug interactions (DDIs) between the mechanism-based inhibitors, erythromycin (ERY) and diltiazem (DTZ), and the CYP3A substrate midazolam (MDZ) is confounded by the time and concentration-dependant clearance of the inhibitors. METHOD Physiologically-based pharmacokinetic (PBPK) models were developed for each drug based on the reported pharmacokinetic (PK) and physiological parameters. Enzyme kinetic parameters (kinact and KI) were estimated in vitro using human liver microsomes for ERY and DTZ, and used to model the time course of changes in the amount of CYP3A. In turn, the amount of CYP3A determined the nonlinear elimination of MDZ, ERY and DTZ and the corresponding DDIs. Simulations were performed using Pharsight® Trial Simulator™. RESULTS kinact and KI were 0.1 min−1 and 15.7 uM, respectively, for ERY, and 0.07 min−1 and 3.2 uM, respectively, for DTZ. The model predicted the nonlinear disposition of ERY and DTZ following single/multiple intravenous or oral doses. The predicted and observed changes in intravenous and oral MDZ AUC following pretreatment with ERY or DTZ are shown below. (See Table) Predicted decrease in CYP3A MDZ AUC ratio (15 mg oral) MDZ AUC ratio (3.5 mg iv) Predicted Observed Predicted Observed ERY 500mg tid × 6 days 60% 4.2 4.4 1.8 2.1 DTZ 60mg × 5 doses 47% 3.2 3.7 1.4 N.A. CONCLUSION The PBPK models incorporating in vitro enzyme parameters predicted the nonlinear PK of ERY and DTZ, and their interactions with MDZ. Clinical Pharmacology & Therapeutics (2005) 79, P34–P34; doi: 10.1016/j.clpt.2005.12.121