Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans

Abstract

1. Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation in humans and the identification of metabolic enzymes of ASV. 2. Following a single oral dose of [(14)C]ASV to humans, the majority of radioactivity (>73% of the dose) was excreted in feces with <1% of the dose recovered in urine. Drug-related radioactivity readily appeared in circulation and the plasma radioactivity was mainly attributed to ASV. A few minor metabolites were observed in human plasma and are not expected to contribute to the pharmacological activity because of low levels. The area under the curve (AUC) values of each circulating metabolite in humans were well below their levels in animals used in the long-term toxicological studies. In bile and feces, intact ASV was a prominent radioactive peak suggesting that both metabolism and direct excretion played important roles in ASV clearance. 3. The primary metabolic pathways of ASV were hydroxylation, sulfonamide hydrolysis and the loss of isoquinoline. In vitro studies with human cDNA expressed CYP enzymes and with human liver microsomes (HLM) in the presence of selective chemical inhibitors demonstrated that ASV was primarily catalyzed by CYP3A4 and CYP3A5.

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

“…Steady state was generally achieved between days 3 and 5 . Asunaprevir is eliminated primarily via CYP3A4‐mediated hepatic metabolism . Asunaprevir is a weak inducer and sensitive substrate of CYP3A4, a moderate inhibitor of CYP2D6, a weak inhibitor and sensitive substrate of organic anion transporting polypeptide (OATP)‐mediated uptake transport and a weak inhibitor of P‐gp …”

Population Pharmacokinetic Analysis for Daclatasvir and Asunaprevir in Japanese Subjects With Chronic Hepatitis C Virus Infection

“…Asunaprevir is eliminated primarily via CYP 3A4‐mediated hepatic metabolism . Asunaprevir is a weak inducer and sensitive substrate of CYP3A4, a moderate inhibitor of CYP2D6, a weak inhibitor and sensitive substrate of organic anion transporting polypeptide(OATP)‐mediated uptake transport and a weak inhibitor of p‐glycoprotein …”

Asunaprevir: An HCV Protease Inhibitor With Preferential Liver Distribution

“…7 Although the low plasma concentrations were suggestive of low bioavailability for ASV, a greater than 2 log 10 reduc- tion in HCV RNA was observed with single-dose ASV. 8 These data, a subsequent mass balance study, 9 and an unpublished absolute bioavailability study suggested that ASV partitioned preferentially into the liver and was a high extraction ratio drug heavily reliant on hepatic metabolism. In the absolute bioavailability study, an oral dose was followed by an intravenous microdose.…”