Abstract
Purpose
Oral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG).
Methods
Both studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03 mg/0.15 mg). In period 2, subjects received EBR (50 mg once daily) for 13 days or GZR (200 mg once daily) for 10 days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females.
Results
There was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC0–∞ and Cmax in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC0–∞ and Cmax GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC0–∞ and for EE and LNG Cmax were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC0–∞ [1.15, 1.32] slightly exceeded the upper bound.
Conclusions
These results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy.
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Acknowledgments
The authors thank all the subjects and clinical research unit staff who participated in this study. The authors also thank Monica Martinho of Merck and Nadia Cardillo Marricco, Daria Stypinski, Xiaopeng Li, and Bruce DeGroot of Celerion for their assistance in this study. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing and editorial assistance was provided by Sally-Anne Mitchell, PhD, and Tim Ibbotson, PhD, of ApotheCom (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Author’s contribution
Conception, design, or planning of the study: JB, LC, ZG, XH, JM, WM, TR, DP, JT, WY.
Acquisition of the data: ZG, JM, WM, TR, WY.
Analysis of the data: H-PF, ZG, XH, EM, WM, WY.
Interpretation of the results: JB, LC, H-PF, ZG, JM, WM, JT, WY.
Drafting of the manuscript: ZG, WM, WY.
Critically reviewing or revising the manuscript for important intellectual content: JB, LC, H-PF, ZG, XH, JM, EM, WM, TR, DP, JT, WY.
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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.
Conflict of interest
WWY, CBS, LC, HPF, JT, JM, EM, XH, RV, ZG, and JRB are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ. WLM was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, at the time the studies were conducted. TR has nothing to disclose.
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All of the subjects gave their written consent to their participation in the study.
Funding
The study was funded by Merck & Co., Inc.
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Marshall, W.L., Feng, HP., Caro, L. et al. No clinically meaningful pharmacokinetic interaction between the hepatitis C virus inhibitors elbasvir and grazoprevir and the oral contraceptives ethinyl estradiol and levonorgestrel. Eur J Clin Pharmacol 73, 593–600 (2017). https://doi.org/10.1007/s00228-017-2216-4
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DOI: https://doi.org/10.1007/s00228-017-2216-4