Pharmacokinetics and tolerability of paritaprevir, a direct acting antiviral agent for hepatitis C virus treatment, with and without ritonavir in healthy volunteers

Abstract

Aims: Paritaprevir is a direct acting antiviral agent for use as part of a multidrug hepatitis C virus infection treatment regimen. To characterize the pharmacokinetics, safety, and tolerability of paritaprevir and determine an optimal dosing regimen for subsequent evaluations, clinical studies were conducted with paritaprevir alone or with ritonavir, a cytochrome P450 3A4 inhibitor anticipated to increase paritaprevir exposure.

Methods: Two phase 1, double-blind, placebo-controlled, parallel group studies were conducted in healthy volunteers (NCT00850044 and NCT00931281). Single dose study participants (n = 87) were randomized to one time administration of either paritaprevir or placebo, or paritaprevir with ritonavir or placebo. Participants (n = 38) enrolled in the multiple dose study received paritaprevir with ritonavir or placebo once or twice daily for 14 days. Pharmacokinetics, safety and tolerability were assessed throughout the study treatment periods.

Results: After single or multiple dose administration, paritaprevir displayed non-linear pharmacokinetics, with maximum plasma concentration and area under the plasma concentration-time curve increasing in a greater than dose proportional manner. Concomitant administration of 100 mg ritonavir increased paritaprevir exposure from a 300 mg dose approximately 30- to 50-fold and extended paritaprevir half-life. The tolerability of paritaprevir was similar with or without ritonavir. Asymptomatic, transient increases in bilirubin were observed but were not associated with abnormalities in other liver function tests.

Conclusions: Paritaprevir exhibits non-linear pharmacokinetics with greater than dose proportional increases in exposure after single or multiple dosing. Co-administration with ritonavir increases paritaprevir exposure and half-life without adversely influencing tolerability.

Keywords: 3D regimen; HCV genotype 1; direct-acting antiviral; hepatitis C; paritaprevir.

© 2015 The British Pharmacological Society.

Figures

Figure 1

Mean plasma concentration–time profile after a single dose of paritaprevir 300 mg ( paritaprevir 300 mg without ritonavir (n=6), paritaprevir 300 mg with ritonavir 100 mg (n=6)). Error bars represent standard deviations

Figure 2

Mean plasma concentration–time profiles after multiple dose administration of paritaprevir with ritonavir once daily and twice daily regimens. Plasma concentrations were measured serially on day 1 and day 14. Trough samples were collected immediately before the morning study drug dose on days 2, 3, 5, 7, 9 and 12. Error bars represent standard deviations. 50/100 mg twice daily (n=8); 100/100 mg twice daily (n=70); 200/100 mg once daily (n=4); 300/100 mg once daily (n=7)

Figure 3

Mean indirect bilirubin measurement–time profiles after multiple dose administration of paritaprevir with ritonavir once daily and twice daily regimens. Error bars represent standard deviations( paritaprevir/ritonavir 50/100 mg twice daily (n=8), paritaprevir/ritonavir 100/100 mg twice daily (n=7), paritaprevir/ritonavir 200/100 mg once daily (n=4), paritaprevir/ritonavir 300/100 mg once daily (n=7)