Pharmacokinetic Interactions and Safety of Coadministration of Glecaprevir and Pibrentasvir in Healthy Volunteers
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Background and Objective
Glecaprevir and pibrentasvir are pangenotypic direct-acting antiviral agents for the treatment of chronic hepatitis C virus infection. The aim of the present study was to evaluate the drug–drug interaction and safety of glecaprevir and pibrentasvir coadministration in healthy volunteers.
In this open-label, randomized, multiple-dose, Phase 1 study in 72 subjects, glecaprevir (100–1200 mg once daily) and pibrentasvir (40–200 mg once daily) were administered alone for 7 days and then in combination for another 7 days. Intensive blood sampling was performed on Days 1, 7, 8, and 14, and pharmacokinetic interactions were assessed using a repeated measures analysis of glecaprevir and pibrentasvir maximum plasma concentration (C max) and area under the curve (AUC).
Coadministration of glecaprevir 400 mg increased pibrentasvir 120 and 40 mg steady-state C max and AUC values to 2.9–6.3-fold, and coadministration of glecaprevir 700 mg increased pibrentasvir 160 mg steady-state C max and AUC24 values to up to sevenfold of the values when pibrentasvir was administered alone. Glecaprevir C max and AUC values during coadministration were less than 1.5-fold of the values when glecaprevir was administered alone. The combination of glecaprevir and pibrentasvir at doses up to 400 mg was well tolerated by the healthy subjects in this study. High glecaprevir exposures at 700 and 1200 mg were associated with grade 2/3 elevations in alanine aminotransferase, aspartate aminotransferase, and/or bilirubin.
Coadministration of pibrentasvir 120 mg with glecaprevir doses up to 400 mg resulted in increases in pibrentasvir exposures without significant changes in glecaprevir exposures in the absence of any clinically significant laboratory abnormalities.
The study was sponsored 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 the AbbVie study team members for assistance in the conduct of the study, and the AbbVie Drug Analysis Department for supporting drug assay development and drug analysis. Medical writing support was provided by Allison Kitten, PhD, and Amy Rohrlack, BS, employees of AbbVie.
Compliance with Ethical Standards
The study was sponsored by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the publication.
Conflict of interest
CL, WZ, AA, AC, and WL are employees of AbbVie and may hold AbbVie stock or stock options. SD is a former employee of AbbVie and may hold AbbVie stock or stock options. Medical writing support was provided by Allison Kitten and Amy Rohrlack, employees of AbbVie.
Research involving human participants
All procedures performed in this study 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. The study protocol was approved by the institutional review board (Vista Medical Center East Institutional Review Board, Waukegan, IL, USA).
Informed consent was obtained from all individual participants included in the study.
- 1.AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.
- 2.European Association for the Study of the Liver. Recommendations on Treatment of Hepatitis C. 2015. http://www.easl.eu/research/our-contributions/clinical-practice-guidelines/detail/recommendations-on-treatment-of-hepatitis-c-2015/report/1.
- 4.Lauffenburger JC, Mayer CL, Hawke RL, Brouwer KL, Fried MW, Farley JF. Medication use and medical comorbidity in patients with chronic hepatitis C from a US commercial claims database: high utilization of drugs with interaction potential. Eur J Gastroenterol Hepatol. 2014;26(10):1073–82. doi: 10.1097/meg.0000000000000152.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Ng T, Reisch T, Middleton T, McDaniel K, Kempf D, Lu L et al. ABT-493, a potent HCV NS3/4A protease inhibitor with broad genotype coverage. 2014. http://www.natap.org/2014/CROI/croi_14.htm. 21st Conference on Retroviruses and Opportunistic Infections, Boston.
- 8.Poordad F, Kwo P, Hassanein T, Asatryan A, Wang S, Wyles D et al. High SVR rates with ABT-493 + ABT-530 in non-cirrhotic patients with HCV genotypes 1, 2, 3 infection. (APASL) 25th Conference of the Asian Pacific Association for the Study of the Liver, Tokyo. 2016. http://www.natap.org/2016/APASL/APASL_02.htm.
- 9.Lalezari J, Gane E, Greenbloom S, Hassaein T, Asatryan A, Ng T et al. 100% SVR4 and favorable safety of ABT-493 + ABT-530 administered for 12 weeks in non-cirrhotic patients with genotypes 4, 5 or 6 infection (SURVEYOR-I). The International Liver Congress 51st Annual Meeting, Barcelona. 2016.Google Scholar
- 15.Kosloski M, Dutta S, Zhao W, Pugatch D, Mensa F, Kort J et al. Pharmacokinetics, safety, and tolerability of next generation direct acting antivirals ABT-493 and ABT-530 in subjects with renal impairment. 2016. http://www.natap.org/2016/EASL/EASL_144.htm. The International Liver Congress, Barcelona.
- 17.Poordad F, Felizarta F, Wang S, Asatryan A, Hassaein T, Aguilar H, et al. High SVR rates with the combination of ABT-493 + ABT-530 for 8 weeks in non-cirrhotic patients with HCV genotype 1 or 2 infection. J Hepatol. 2016;64:S768.Google Scholar
- 18.Gane E, Lalezari J, Asatryan A, Greenbloom S, Hassaein T, Ng T, et al. 100% SVR4 and favorable safety of ABT-493 + ABT-530 administered for 12 weeks in non-cirrhotic patients with genotypes 4, 5, or 6 infection (SURVEYOR-I). J Hepatol. 2016;64:S758.Google Scholar
- 21.Polepally AR, Mensing S, Khatri A, Beck D, Liu W, Awni WM, et al. Dose- and formulation-dependent non-linear pharmacokinetic model of paritaprevir, a protease inhibitor for the treatment of hepatitis C virus infection: combined analysis from 12 phase I studies. Clin Pharmacokinet. 2016. doi: 10.1007/s40262-016-0385-4.PubMedCentralGoogle Scholar
- 23.Menon RM, Klein CE, Podsadecki TJ, Chiu YL, Dutta S, Awni WM. Pharmacokinetics and tolerability of paritaprevir, a direct acting antiviral agent for hepatitis C virus treatment, with and without ritonavir in healthy volunteers. Br J Clin Pharmacol. 2016;81(5):929–40. doi: 10.1111/bcp.12873.CrossRefPubMedPubMedCentralGoogle Scholar