Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment.

Abstract

This study characterized the effects of hepatic impairment on the pharmacokinetics and safety of glecaprevir and pibrentasvir, two direct-acting antivirals used for treatment of chronic HCV infection. HCV-negative subjects with normal hepatic function, or with mild (Child-Pugh [CP]-A), moderate (CP-B), or severe (CP-C) hepatic impairment received single doses of pibrentasvir 120mg alone or with glecaprevir 200mg or 300mg (n = 6/functional group/dose). Plasma pharmacokinetics and protein binding were evaluated. Doses were separated by ≥ 14days of washout. For the approved combination of glecaprevir 300mg with pibrentasvir 120mg, glecaprevir AUC was increased by 33% (CP-A), to 2.0-fold (CP-B), and to 11-fold (CP-C) relative to normal subjects; pibrentasvir AUC was ≤ 26% different (CP-A or CP-B) and increased to 2.1-fold (CP-C). For glecaprevir 200mg with pibrentasvir 120mg, glecaprevir AUC was increased by 80% (CP-A) or to 2.8-fold (CP-B), while pibrentasvir AUC was unaffected in the same subjects (≤ 12% difference). Pibrentasvir 120mg alone AUC increased 51% (CP-A), 31% (CP-B), and to 5.2-fold (CP-C). The unbound fraction of glecaprevir was higher in CP-C subjects than normal subjects and pibrentasvir protein binding was similar across groups. The most common adverse event was headache; no events were serious. This study supported evaluation of the glecaprevir 300mg with pibrentasvir 120-mg combination in HCV-infected subjects with CP-A hepatic impairment without dose adjustment. Elevated glecaprevir and/or pibrentasvir exposures are expected in HCV-infected patients with CP-B or CP-C hepatic impairment.