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

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.

Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials

“…This analysis showed that ribavirin coadministration did not affect the pharmacokinetics of any of the DAAs in HCV genotype 1-infected subjects, as ribavirin was not identified as a covariate in any of the analyses. Ribavirin values of clearance and volume parameters estimated from the population pharmacokinetic analysis were in close agreement with those reported in the population pharmacokinetic analysis of phase Ib and II studies of the 3D regimen [25] and in the literature [32,33], suggesting that the pharmacokinetics of ribavirin were not altered when coadministered with the 3D regimen. The weight-based ribavirin dosing used in the clinical trials that contributed to the present analysis provided consistent exposures across the various covariates.…”

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

“…21 Similarly, paritaprevir and grazoprevir AUC 24 values in Asian subjects were 30% and 50% higher, respectively, compared to those in whites. [22][23][24] Increased exposures in Asian sub-jects may lead to potential adverse events including alanine aminotransferase and total bilirubin elevations. Alanine aminotransferase elevations have been observed in a small proportion (1%) of patients administered currently approved treatment regimens containing the HCV protease inhibitors paritaprevir/ritonavir, grazoprevir, and asunaprevir.…”

Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus Three Direct-Acting Antiviral Regimen: Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir

“…For M1 only, prediction of UGT inhibition was also based on the ratio (R 1 ) of unbound C max to in vitro enzyme K i . Assumptions are as follows: f m of P450 probe substrates is assumed to be 0.99 (represents an upper estimate of the enzyme contribution; Brown et al, 2005), F g of midazolam as a CYP3A probe substrate was assumed to be 0.53 (Simcyp, version 14.1; Certara, Princeton, NJ), and K a values used for each drug were previously reported (Mensing et al, 2016).…”