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Application of Exposure-Response Analyses to Establish the Pharmacodynamic Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing Regimen for the Treatment of HCV Infection

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Abstract

The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir C trough, paritaprevir C max, and ritonavir C max. In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product’s labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir C trough for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR12). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.

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Acknowledgments

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. The authors thank the clinical sites and investigators and AbbVie study team members Peter Probst, Pamela Watson, Natalie Hycner, and Lisa Hernandez for assistance with the conduct of the study and/or report writing. The authors thank Meher M. Dustoor, PhD, and Lamara D. Shrode, PhD, CMPP, of JB Ashtin for editorial assistance (writing, technical editing, and proofreading) in preparing this manuscript for publication on behalf of AbbVie Inc.

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Authors and Affiliations

  1. Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc, North Chicago, Illinois, USA

    Akshanth R. Polepally, Patrick J. Marroum, Mukul Minocha, Amit Khatri, Walid M. Awni & Rajeev M. Menon

  2. Biometrics, AbbVie Inc, North Chicago, Illinois, USA

    Haoyu Wang & Balakrishna Hosmane

  3. Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co, Ludwigshafen am Rhein, Germany

    Sven Mensing

  4. Infectious Disease Development, AbbVie Inc, North Chicago, Illinois, USA

    Thomas J. Podsadecki & Daniel E. Cohen

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  1. Akshanth R. Polepally
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Contributions

A.R.P. contributed to the design of the research, performed research and analysis, interpreted the data, and wrote the manuscript. H.W. contributed to the design of the research, performed research and analysis, interpreted the data, and critically reviewed the manuscript. P.J.M. contributed to the design of the research, interpreted the data, and critically reviewed the manuscript. M.M. contributed to the analysis, interpreted the data, and wrote the manuscript. B.H. performed the research and critically reviewed the manuscript. A.K. contributed to the design of the research, performed analysis, interpreted the data, and critically reviewed the manuscript. S.M. contributed to the analysis, interpreted the data, and critically reviewed the manuscript. T.J.P. contributed to the design of the research, analyzed and interpreted the data, and critically reviewed the manuscript. D.E.C. contributed to the design of the research, analyzed and interpreted the data, and critically reviewed the manuscript. W.M.A. contributed to the design of the research, analyzed and interpreted the data, and critically reviewed the manuscript. R.M.M. contributed to the design of the research, analyzed and interpreted the data, and critically reviewed the manuscript.

Corresponding author

Correspondence to Rajeev M. Menon.

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Disclosure

A.R.P., H.W., P.J.M., M.M., B.H., A.K., T.J.P, D.E.C., W.M.A., and R.M.M are employees/contractors of AbbVie Inc. and own stock or stock options. S.M. is a full-time employee of AbbVie Deutschland GmbH & Co KG and owns stock or stock options.

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Polepally, A.R., Wang, H., Marroum, P.J. et al. Application of Exposure-Response Analyses to Establish the Pharmacodynamic Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing Regimen for the Treatment of HCV Infection. AAPS J 19, 1523–1535 (2017). https://doi.org/10.1208/s12248-017-0115-3

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