Metabolism and Disposition of Pan-Genotypic Inhibitor of Hepatitis C Virus NS 5 A Ombitasvir in Humans s

Ombitasvir (also known asABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a threedirect-actingantiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance,metabolism, and dispositionof ombitasvir in humanswithout coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metaboliteswere primarily eliminated in feces (90.2%of dose),mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450–mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steadystate concentration measurement of ombitasvir metabolites by liquid chromatography–mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination