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Exposure–Response Relationship for Ombitasvir and Paritaprevir/Ritonavir in Hepatitis C Virus Subgenotype 1b-Infected Japanese Patients in the Phase 3 Randomized GIFT-I Study

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Abstract

Introduction

The all-oral 2 direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once a day has been evaluated in hepatitis C virus subgenotype 1b-infected Japanese adults in the GIFT-I study. The aim of this analysis was to evaluate potential relationships between DAA exposures and laboratory abnormalities/adverse events of peripheral edema in patients in GIFT-I.

Methods

The GIFT-I study consisted of a randomized, double-blind, placebo-controlled substudy in patients without cirrhosis and an open-label substudy in patients with compensated cirrhosis. Patients received ombitasvir/paritaprevir/ritonavir for 12 weeks. Exposure–response relationships between individual components of the ombitasvir/paritaprevir/ritonavir regimen and clinical parameters of interest were explored using pharmacokinetic and clinical data from patients in the study. Graphical analyses were performed. For events that occurred in at least 10 patients (total bilirubin elevation ≥grade 2 and peripheral edema ≥grade 1), multivariate logistic regression analyses were used to identify significant relationships between predictor variables (drug exposures) and response variables (probability of adverse events or laboratory abnormalities), with consideration for the effect of potential covariates and baseline status of response variables.

Results

Data from 321 noncirrhotic and 42 compensated cirrhotic patients were analyzed. There were 14 events of peripheral edema (10 at grade 1 and 4 at grade 2) in patients who received concomitant administration of calcium channel blockers and ombitasvir/paritaprevir/ritonavir. There was no apparent relationship between the incidences of peripheral edema and exposures of paritaprevir, ombitasvir, or ritonavir. There was a shallow relationship between total bilirubin elevation and exposures of paritaprevir which is an inhibitor of bilirubin transporter organic anion-transporting polypeptide 1B. Based on graphical analyses, exposures of paritaprevir, ombitasvir, or ritonavir were weakly associated with hemoglobin decrease, but not associated with post baseline alanine aminotransferase or aspartate aminotransferase elevations.

Conclusions

In Japanese patients, there were no associations or only shallow relationships between DAA exposures and peripheral edema or laboratory abnormalities. Consequently, therapeutic drug monitoring is not expected to be beneficial in managing patients on the 2-DAA regimen.

Trial registration

ClinicalTrials.gov identifier, NCT02023099.

Funding

AbbVie Inc.

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Acknowledgments

Sponsorship and article processing charges for this study were funded by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the publication. The authors thank the clinical sites and investigators and AbbVie study team members for assistance with the conduct of the study. Medical writing support was provided by Amy Rohrlack, a medical writer employed by AbbVie. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Disclosures

Sathej Gopalakrishnan is an employee of AbbVie and holds AbbVie stock or stock options. Amit Khatri is an employee of AbbVie and holds AbbVie stock or stock options. Sven Mensing is an employee of AbbVie and holds AbbVie stock or stock options. Rebecca Redman is an employee of AbbVie and holds AbbVie stock or stock options. Rajeev Menon is an employee of AbbVie and holds AbbVie stock or stock options. Jiuhong Zha is an employee of AbbVie and holds AbbVie stock or stock options.

Compliance with Ethics Guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. The study protocol was approved by all institutional review boards and informed consent was obtained from all patients for being included in the study.

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Authors and Affiliations

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

    Sathej Gopalakrishnan & Sven Mensing

  2. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA

    Amit Khatri, Rajeev Menon & Jiuhong Zha

  3. Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA

    Rebecca Redman

Authors
  1. Sathej Gopalakrishnan
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  2. Amit Khatri
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  3. Sven Mensing
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  5. Rajeev Menon
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  6. Jiuhong Zha
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Corresponding author

Correspondence to Jiuhong Zha.

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Gopalakrishnan, S., Khatri, A., Mensing, S. et al. Exposure–Response Relationship for Ombitasvir and Paritaprevir/Ritonavir in Hepatitis C Virus Subgenotype 1b-Infected Japanese Patients in the Phase 3 Randomized GIFT-I Study. Adv Ther 33, 670–683 (2016). https://doi.org/10.1007/s12325-016-0320-y

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  • DOI: https://doi.org/10.1007/s12325-016-0320-y

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