Clinical Pharmacokinetics and Drug–Drug Interactions of Elbasvir/Grazoprevir

Abstract

Elbasvir and grazoprevir, in a fixed-dose combination of 50 and 100 mg, respectively, have received approval to be administered orally once daily, with or without ribavirin, for the treatment of chronic hepatitis C virus (HCV) infections. The absorption characteristics of elbasvir and grazoprevir have been adequately summarized, although differences were observed for grazoprevir (e.g., increased exposure at steady state in patients), but not elbasvir, between healthy and HCV-infected subjects. Inconsistencies with respect to absorption were also reported on the effects of food or acid reducers (famotidine or pantoprazole) in the literature. Many distribution characteristics of elbasvir and grazoprevir have been obtained from in vitro models, using incubation conditions that were in many cases inconsistent with normal physiological conditions in humans. Elbasvir and grazoprevir appear to undergo modest hepatic metabolism and are excreted primarily unchanged (~ 80% parent drug found) in feces. Both elbasvir and grazoprevir are substrates of cytochrome P450 (CYP) 3A4 enzyme, but mechanistic experiments were lacking to demonstrate the role of other enzymes and the precise relative % contribution of CYP3A4. The pharmacokinetics of elbasvir and grazoprevir have been characterized in various special populations (elderly, male vs. female, Caucasian vs. Asian, renal impairment, and hepatic impairment). Other than moderate and severe hepatic impairment where administrations are contraindicated, no dose adjustments are required for both drugs in these special patient populations. The available drug–drug interaction data provided some consistency between in vitro and in vivo observations and, in some instances, can provide predictions of likely clinically relevant scenarios.