Improved prediction of drug interactions using in vivo Ki

Abstract

Drug-drug interactions are a leading cause of death in the U.S. CYP3A metabolism is the predominant pathway for drug metabolism. Itraconazole (ITZ) alters CYP3A activity resulting in clinically significant drug interactions. To date, in vitro studies have not been successful in predicting the magnitude of CYP3A drug interactions in humans. We validated the venous equilibrium model using a physiologically stable, chronically catheterized rat, measuring MDZ disposition from multiple, simultaneous aortic and hepatic vein blood samples after duodenal administration. MDZ clearance and hepatic availability were scaled to humans, and predicted published human MDZ pharmacokinetic parameters. MDZ disposition in vivo was characterized in rats after a single and multiple doses of ITZ. MDZ and ITZ concentrations were quantified by LC-MS. In vivo estimates from rat model for KM of MDZ were 5.7 ± 0.6 ug/ml (n=8) and 1.1 ± 0.2 ug/ml (n=10) in the presence and absence of 0.71 uM ITZ. The extent of inhibition (AUCI/AUC) reported in humans of MDZ clearance by ITZ was 3.2-fold after a single dose (ITZ CpSS, AVG= 0.17 uM) and 7-fold after 6 daily doses of 200 mg (ITZ CpSS AVG = 0.71 uM). Based upon the effects of ITZ on MDZ pharmacokinetics in rats, the extent of MDZ inhibition was 2.4- and 7-fold, respectively. The estimate for the ITZ inhibition constant in rats (Ki) accurately predicted the extent of inhibition of MDZ elimination in humans from previously published studies. Clinical Pharmacology & Therapeutics (2004) 75, P81–P81; doi: 10.1016/j.clpt.2003.11.308