Abstract
Background and Objective
Hepatitis C virus (HCV) infection is of considerable clinical concern in Japan. We modeled the population pharmacokinetics of an oral interferon-free, direct-acting antiviral agent (DAA) regimen (i.e., the 2D regimen) recently approved for the treatment of chronic HCV genotype 1 infection as a new option for affected Japanese patients.
Methods
Using data from a phase III clinical trial (GIFT-I) that enrolled Japanese patients with HCV genotype 1b infection, population pharmacokinetic models were developed for the drugs that comprise the 2D regimen: paritaprevir, ombitasvir, and ritonavir. Demographic and clinical covariates with potential to influence 2D pharmacokinetics were evaluated for their effects on drug exposures. Proposed models were assessed using goodness-of-fit plots, visual predictive checks, and bootstrap evaluations.
Results
One-compartment models with first-order absorption and elimination adequately described the population pharmacokinetics of paritaprevir, ombitasvir, and ritonavir. On average, patients with cirrhosis had approximately 95–145 % higher, 19–24 % lower, and 58–68 % higher exposures of paritaprevir, ombitasvir, and ritonavir, respectively. Female patients had 58–81 % higher ombitasvir exposures, whereas patients with mild renal impairment (creatinine clearance 75 mL/min) had 9–14 % higher ombitasvir exposures than did patients with normal renal function (creatinine clearance 105 mL/min). The DAA exposure values were comparable between responders and non-responders.
Conclusion
Population pharmacokinetic modeling did not reveal any patient-related or clinical parameters that would require dose adjustment of the 2D regimen when used for the treatment of HCV genotype 1b infection in Japanese patients.
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Acknowledgments
The authors thank Zhongging (Will) He (who built the NONMEM® datasets) and Rochelle M. Jurasz (who assisted in writing the population pharmacokinetic report) of AbbVie for their contributions, and Crystal Murcia, PhD, and Meher M. Dustoor, PhD, Lamara D. Shrode, PhD, CMPP, of The JB Ashtin Group, Inc., for assistance in preparing this manuscript for publication.
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This work was supported by AbbVie Inc. AbbVie contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the manuscript for publication.
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Sathej M. Gopalakrishnan, Akshanth R. Polepally, Sven Mensing, Amit Khatri, and Rajeev M. Menon are AbbVie employees and may hold AbbVie stocks or options.
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S. M. Gopalakrishnan and A. R. Polepally contributed equally to this manuscript.
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Gopalakrishnan, S.M., Polepally, A.R., Mensing, S. et al. Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection. Clin Pharmacokinet 56, 1–10 (2017). https://doi.org/10.1007/s40262-016-0423-2
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DOI: https://doi.org/10.1007/s40262-016-0423-2