Paritaprevir (also known as
ABT-450), a potent NS3-4A
serine protease inhibitor [identified by AbbVie (North Chicago, IL) and Enanta
Pharmaceuticals (Watertown, MA)] of the hepatitis C virus (HCV), has been developed in combination with
ombitasvir and
dasabuvir in a three-direct-acting
antiviral agent (DAA) oral regimen for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of
paritaprevir in humans. After the administration of a single 200-mg oral dose of [(14)C]
paritaprevir coadministered with 100 mg of
ritonavir to four male healthy volunteers, the mean total percentage of the administered radioactive dose recovered was 96.5%, with recovery in individual subjects ranging from 96.0% to 96.9%. Radioactivity derived from [(14)C]
paritaprevir was primarily eliminated in feces (87.8% of the dose). Radioactivity recovered in urine accounted for 8.8% of the dose. The biotransformation of
paritaprevir in humans involves: 1) P450-mediated oxidation on the olefinic linker, the phenanthridine group, the methylpyrazinyl group, or combinations thereof; and 2)
amide hydrolysis at the acyl
cyclopropane-
sulfonamide moiety and the
pyrazine-2-carboxamide moiety.
Paritaprevir was the major component in plasma [90.1% of total radioactivity in plasma, AUC from time 0 to 12 hours (AUC0-12hours) pool]. Five minor metabolites were identified in plasma, including the metabolites M2, M29, M3, M13, and M6; none of the metabolites accounted for greater than 10% of the total radioactivity.
Paritaprevir was primarily eliminated through the biliary-fecal route followed by microflora-mediated
sulfonamide hydrolysis to M29 as a major component in feces (approximately 60% of dose). In summary, the biotransformation and clearance pathways of
paritaprevir were characterized, and the structures of metabolites in circulation and excreta were elucidated.