Pharmacokinetic Enhancement of the Hepatitis C Virus Protease Inhibitors VX-950 and SCH 503034 by Co-Dosing with Ritonavir

Abstract

Inhibitors of hepatitis C virus (HCV) protease have shown marked antiviral activity in short-term clinical studies in HCV-infected individuals. The interaction of the investigational HCV protease inhibitors VX-950 and SCH 503034 with ritonavir, a potent inhibitor of cytochrome P450 3A, was studied in vitro and in vivo. In rat and human liver microsomes, the metabolism of VX-950 and SCH 503034 was strongly inhibited by the presence of 4 microM ritonavir. Upon co-dosing either VX-950 or SCH 503034 with ritonavir in rats, plasma exposure of the HCV protease inhibitors was increased by > 15-fold, and plasma concentrations 8 h after dosing were increased by > 50-fold. A human pharmacokinetic model of VX-950 co-administered with low-dose ritonavir suggested that improved efficacy and/or dosing convenience may be feasible by pharmacokinetic enhancement with ritonavir.