Pharmacokinetics, Safety, and Tolerability of Glecaprevir and Pibrentasvir in Healthy White, Chinese, and Japanese Adult Subjects

Abstract

Glecaprevir and pibrentasvir are direct-acting antiviral agents being developed as combination therapy for the treatment of chronic hepatitis C virus infection. The aim of the present studies was to assess the effect of race and ethnicity (white, Han Chinese, Japanese) on the pharmacokinetics and safety of multiple oral doses of glecaprevir and pibrentasvir given alone and in combination. Two multiple-dose, single-center, phase 1 studies were conducted in healthy adult male and female subjects (n = 170) of respective Asian and white race/ethnicity. Glecaprevir (100, 200, 300, or 700 mg once daily) and pibrentasvir (80, 120, or 160 mg once daily) were administered alone for 7 days followed by the combination of both direct-acting antiviral agents for another 7 days. Intensive blood sampling was performed, and pharmacokinetic parameters were estimated by noncompartmental analyses. ANOVA was employed to evaluate for differences of steady-state glecaprevir and pibrentasvir exposures between Asian (Japanese or Han Chinese) and white subjects. Glecaprevir and pibrentasvir exposures in Han Chinese and Japanese were similar to those in whites across dose levels. The nonlinear dose-exposure relationships for glecaprevir and pibrentasvir were similar across Japanese, Han Chinese, and white subjects, and the safety profiles of the agents were comparable across these groups. The results of these studies demonstrate that race/ethnicity has no clinically meaningful impact on direct-acting antiviral agent exposures, safety, or tolerability of the glecaprevir and pibrentasvir combination. This is supported in part by the large global registration program of the pangenotypic, coformulated fixed-dose glecaprevir/pibrentasvir regimen and allows for inclusion of diverse ethnic populations.

Glecaprevir/pibrentasvir for patients with chronic hepatitis C virus infection: Real‐world effectiveness and safety in Taiwan

“…The proportion of pruritus in our study (7.8%) was similar to reports from Japan (6.0%‐7.3%), but tended to be higher than Western's studies (4.7%) . Although a recent pharmacokinetic study showed no differences in GLE/PIB exposure among White, Chinese, and Japanese healthy adults, the maximum plasma concentration and the area under plasma concentration‐time curve were significantly higher in Chinese and Japanese than those in Whites when GLE or PIB was administered alone . In addition to race/ethnicity, other factors, such as age, sex.…”

“…18,19,23,33,34 Although a recent pharmacokinetic study showed no differences in GLE/PIB exposure among White, Chinese, and Japanese healthy adults, the maximum plasma concentration and the area under plasma concentration-time curve were significantly higher in Chinese and Japanese than those in Whites when GLE or PIB was administered alone. 39…”

Translation of In Vitro Transport Inhibition Studies to Clinical Drug-Drug Interactions for Glecaprevir and Pibrentasvir

“…When coadministered with glecaprevir, pibrentasvir exposures are higher than for pibrentasvir alone in a mechanism attributed to inhibition of intestinal P-gp and/or BCRP by glecaprevir. These increases were similar for glecaprevir 200-400 mg doses, increasing the pibrentasvir AUC to 3.0to 3.5-fold and suggesting a saturation of this inhibition in the clinical dose range (Lin et al, 2017(Lin et al, , 2018; potent inhibition of intestinal P-gp with glecaprevir 300 mg was confirmed in the dabigatran etexilate study. Similarly, substantial OATP1B1/3 interactions for glecaprevir 300 mg were observed in subsequent studies with simvastatin and lovastatin (Mavyret, 2019).…”

A case report of glecaprevir/pibrentasvir-induced severe hyperbilirubinemia in a patient with compensated liver cirrhosis

“…[13] The mean value of glecaprevir maximum plasma concentration level was reported as 1,150 to 1,390 ng/mL in normal healthy adult subjects. [14] An analysis of previous phase 2 and 3 trials showed that plasma drug concentration levels were 2.2-fold higher in patients with cirrhosis than patients without cirrhosis. [4] Even considering the higher drug concentration level in cirrhotic patients, our patient had about 13- to 16-fold higher plasma drug concentration level (18,500 ng/mL) when hyperbilirubinemia was diagnosed.…”