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Clinical Pharmacokinetics

, Volume 57, Issue 11, pp 1407–1419 | Cite as

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Hepatitis C Virus-Infected Cirrhotic and Non-cirrhotic Patients: Analyses Across Nine Phase III Studies

  • Sathej Gopalakrishnan
  • Sven Mensing
  • Rajeev M. Menon
  • Jiuhong Zha
Original Research Article

Abstract

Background

The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations.

Objective

The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis (‘non-cirrhotic’) and with compensated cirrhosis (‘cirrhotic’), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen ± ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities.

Methods

Pharmacokinetic data from nine clinical studies (~ 1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate–parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one-compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model.

Results

The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30–60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients.

Conclusion

These differences did not warrant dose adjustments for the DAAs when used in HCV-infected patients with compensated cirrhosis.

Notes

Acknowledgements

The authors acknowledge Eva Dölger and Doerthe Eckert of AbbVie for their assistance with the manuscript figures and Amy Rohrlack of AbbVie for her medical writing support.

Compliance with Ethical Standards

Funding

Financial support was provided by AbbVie. All authors participated in the interpretation of data, review, and approval of the manuscript.

Conflict of interest

Sathej Gopalakrishnan, Sven Mensing, Rajeev M. Menon, and Jiuhong Zha are employees of AbbVie and may hold AbbVie stock or stock options. Medical writing support was provided by Amy Rohrlack, an AbbVie employee.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the studies that were included in this analysis.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Sathej Gopalakrishnan
    • 1
  • Sven Mensing
    • 1
  • Rajeev M. Menon
    • 2
  • Jiuhong Zha
    • 2
  1. 1.Clinical Pharmacology and PharmacometricsAbbVie Deutschland GmbH & Co. KGLudwigshafen am RheinGermany
  2. 2.Clinical Pharmacology and PharmacometricsAbbVie Inc.North ChicagoUSA

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