Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies

Abstract

Direct-acting antiviral agents (DAAs) are established as the standard of care for chronic hepatitis C virus (HCV) infection. One of the newest additions to the HCV arsenal is an oral three-DAA combination therapy (i.e., the 3D regimen) that does not require concomitant use of pegylated interferon. The clinical development program for the 3D regimen has yielded a robust dataset that is inclusive of various dosing schemes and a diverse patient population. Using data from nine phase 1b/2a/2b studies that enrolled patients with HCV genotype 1 infection, population pharmacokinetic models were developed for each component of the 3D regimen (ombitasvir, paritaprevir, ritonavir, and dasabuvir) and for ribavirin, an adjunctive therapy used to enhance therapeutic efficacy in some populations. Formulation effects, accumulation, relative bioavailability, and interactions between DAAs were assessed during model development, and demographic and clinical covariates were identified and evaluated for their effects on drug exposures. Proposed models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Population pharmacokinetic models adequately described their respective plasma concentration-time data with precise and reliable model parameter estimates and with good predictive performance. Covariates, including age, sex, body weight, cytochrome P450 2C8 inhibitor use, non-Hispanic ethnicity, and creatinine clearance, were associated with apparent clearance and/or apparent volume parameters; however, the magnitude of effect on drug exposure was modest and not considered to be clinically significant. No patient-related or clinical parameters were identified that would necessitate dose adjustment of the 3D regimen in patients with HCV genotype 1 infection.

Keywords: 2D regimen; 3D regimen; direct-acting antiviral; dosing recommendations; population pharmacokinetics.

Conflict of interest statement

All authors are AbbVie employees and may hold AbbVie stocks or options.

Figures

Fig. 1

Dose-related changes in relative bioavailability of paritaprevir for the spray-dried dispersion (SDD) tablet and hard gelatin capsule (HGC) formulations

Fig. 2

Population pharmacokinetic evaluations. Model-derived estimates of steady-state maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) for covariates identified as significantly associated with apparent clearance or apparent volume parameters for paritaprevir (150 mg once daily), ombitasvir (25 mg once daily), dasabuvir (400 mg twice daily), ritonavir (100 mg once daily), and ribavirin (600 mg twice daily). A ratio of 1.0 indicates similar values between the subgroup analyzed and the rest of the patient population. Error bars represent the 95% confidence intervals. Weight groups for ombitasvir analyses were stratified as 89 and 69 kg, and age was plotted for 58 and 38 years. Weight groups for ribavirin analyses were stratified as 89 and 69 kg, and creatinine clearance (CrCL) was plotted for 65 and 120 mL/min. BWT body weight, CYP2C8 cytochrome P450 2C8

Fig. 3

Visual predictive checks for population pharmacokinetic models. Filled circles represent observed median values (5th and 95th percentile error bars). The simulated median is represented by a solid line and the associated 90% interval of the simulated median by grey shading. The simulated 5th and 95th percentiles are represented by dashed lines and the associated 90% interval of the simulated 5th and 95th percentile by grey shading. The profile for ribavirin starts 2 weeks into the treatment period, thus illustrating steady-state