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.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12325-016-0320-y/MediaObjects/12325_2016_320_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12325-016-0320-y/MediaObjects/12325_2016_320_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12325-016-0320-y/MediaObjects/12325_2016_320_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12325-016-0320-y/MediaObjects/12325_2016_320_Fig4_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12325-016-0320-y/MediaObjects/12325_2016_320_Fig5_HTML.gif)
Similar content being viewed by others
References
World Health Organization (WHO). Hepatitis C—Fact Sheet No 164. April 2014. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed 10 Mar 2016.
Dore GJ, Ward J, Thursz M. Hepatitis C disease burden and strategies to manage the burden (guest editors Mark Thursz, Gregory Dore and John Ward). J Viral Hepatol. 2014;21(Suppl 1):1–4.
Freeman AJ, Dore GJ, Law MG, Thorpe M, Von Overbeck J, Lloyd AR, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology. 2001;34(4 Pt 1):809–16.
Chung H, Ueda T, Kudo M. Changing trends in hepatitis C infection over the past 50 years in Japan. Intervirol. 2010;53(1):39–43.
Wu S, Kanda T, Nakamoto S, Jiang X, Miyamura T, Nakatani SM, et al. Prevalence of hepatitis C virus subgenotypes 1a and 1b in Japanese patients: ultra-deep sequencing analysis of HCV NS5B genotype-specific region. PLoS One. 2013;8(9):e73615.
DeGoey DA, Randolph JT, Liu D, Pratt J, Hutchins C, Donner P, et al. Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem. 2014;57(5):2047–57.
VIEKIRA PAK® (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [package insert]. North Chicago, IL; AbbVie Inc., 2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206619s010lbl.pdf. Accessed 01 Mar 2016.
Kumada H, Chayama K, Rodrigues L Jr, Suzuki F, Ikeda K, Toyoda H, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology. 2015;62:1037–46.
Gopalakrishnan S, Polepally A, Mensing S, Menon R, Khatri A. Population pharmacokinetics of paritaprevir, ombitasvir and ritonavir in Japanese subjects with HCV genotype 1b infection [abstract 39]. In: Reviews in antiviral therapy & infectious diseases 2015;4:43–44. 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, Washington, DC, 26–28 May, 2015.
R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/. Accessed 10 Mar 2016.
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49(12):1373–9.
Hosmer DW, Lemeshow S. Applied logistic regression. 2nd ed. New York: Wiley; 2004.
NORVASC® (amlodipine besylate tablets) [package insert]. New York, NY; Pfizer Labs, a division of Pfizer Inc., 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019787s059lbl.pdf. Accessed 11 Nov 2015.
Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A, et al. Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol. 2015;63(1):20–9.
Badri PS, King JR, Polepally AR, McGovern BH, Dutta S, Menon RM. Dosing recommendations for concomitant medications during 3D anti-HCV therapy. Clin Pharmacokinet. 2016;55(3):275–95.
OLYSIO® (simeprevir capsules) [package insert]. Titusville, NJ; Janssen Therapeutics, Division of Janssen Products, LP, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205123s005lbl.pdf. Accessed 11 Nov 2015.
Menon RM, Klein CE, Podsadecki TJ, Chiu YL, Dutta S, Awni WM. Pharmacokinetics and tolerability of paritaprevir, a direct-acting antiviral agent for HCV treatment, with and without ritonavir in healthy volunteers. Br J Clin Pharmacol. 2015. doi:10.1111/bcp.12873.
Bow DAJ, Liu J, Kavetskaia O, Menon R, de Morais SM, Nijsen M. 2014. A mechanistic non-clinical assessment of drug-drug interactions (metabolism and transporters) with the hepatitis C virus (HCV) regimen: ABT-450/r, ombitasvir and dasabuvir, abstr AASLD/EASL Special Conference on Hepatitis C, New York, NY, October 3–5, 2014.
Menon R, Badri P, Khatri A, Wang T, Bow S, Polepally A. 2014. ABT–450/ritonavir + ombitasvir + dasabuvir: drug interactions mediated by transporters, abstr 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, Washington, DC, May 19–21, 2014.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Enhanced content
To view enhanced content for this article go to http://www.medengine.com/Redeem/9884F0605BC31A47.
Rights and permissions
About this article
Cite this article
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
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-016-0320-y