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
Journal Title: The AAPS Journal - Year 2016, Vol 18, Issue 1
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.
Authors and Affiliations
Sven Mensing, Akshanth R. Polepally, Denise König, Amit Khatri, Wei Liu, Thomas J. Podsadecki, Walid M. Awni, Rajeev M. Menon, Sandeep Dutta
Keywords
Related Articles
- EP ID EP680836
- DOI 10.1208/s12248-015-9846-1
- Views 55
- Downloads 0
Resveratrol Suppresses T0901317-Induced Hepatic Fat Accumulation in Mice
Liver X receptor (LXR) has been identified as a potential target for treatment of atherosclerosis and diabetes. Activation of LXR, however, is associated with increased lipogenesis and fat accumulation in the liver. The...
An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence
The online version of this article (doi:10.1208/s12248-016-9873-6) contains supplementary material, which is available to authorized users.
Micro-Flow Imaging: Flow Microscopy Applied to Sub-visible Particulate Analysis in Protein Formulations
The need to monitor, measure, and control sub-visible proteinaceous particulates in biopharmaceutical formulations has been emphasized in recent publications and commentaries. Some of these particulates can be highly tra...
Workshop Report and Follow-Up—AAPS Workshop on Current Topics in GLP Bioanalysis: Assay Reproducibility for Incurred Samples—Implications of Crystal City Recommendations
The Conference Report of the 3rd AAPS/FDA Bioanalytical Workshop (Crystal City III) endorsed the concept that assay methods supporting bioanalytical data in submissions must demonstrate assay reproducibility by using inc...
Procedural elements involved in maintaining bioanalytical data integrity for good laboratory practices studies and regulated clinical studies
This article describes procedural elements involved in ensuring the integrity of bioanalytical data. These elements can be divided into 3 areas. First, there are those ensuring the integrity of the analyte until analysis...