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Pharmacokinetic and pharmacodynamic interactions between the hepatitis C virus protease inhibitor, boceprevir, and the oral contraceptive ethinyl estradiol/norethindrone

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE).

Methods

A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days.

Results

Coadministration of boceprevir with EE/NE did not affect NE AUC0–24 but slightly reduced NE C max. Geometric mean ratios (GMRs) for NE AUC0–24 and C max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90 % confidence interval (CI), 0.87–1.06) and 0.83 (90 % CI, 0.76–0.90). Coadministration of boceprevir with EE/NE reduced EE AUC0–24 and C max by 26 and 21 %, with GMRs of 0.74 (90 % CI, 0.68–0.80) and 0.79 (90 % CI, 0.75–0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained <1 ng/ml during the luteal phase. Adverse events reported in this study were consistent with the well-established safety profile of boceprevir.

Conclusion

Serum progesterone, LH, and FSH levels indicate that ovulation was suppressed during coadministration of boceprevir with EE/NE. Coadministration of boceprevir with combined oral contraceptives containing EE and ≥1 mg of NE is therefore unlikely to alter contraceptive effectiveness. The ovulation suppression activity of oral contraceptives containing lower doses of NE, and of other forms of hormonal contraception during coadministration with boceprevir, has not been established.

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Acknowledgments

Medical writing and editorial assistance were provided by Tim Ibbotson, PhD, and Bianca Ruzicka, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.

Conflict of interest

This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.

TO had a financial relationship within the last 12 months relevant to this presentation with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. H-PF, CS, JW, and JB are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. WL is a former employee of Merck Sharp and Dohme Corp, a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA.

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Authors and Affiliations

  1. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA

    Wen H. Lin, Hwa-Ping Feng, Craig R. Shadle, John A. Wagner & Joan R. Butterton

  2. Celerion, Phoenix, AZ, USA

    Terry O’Reilly

Authors
  1. Wen H. Lin
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  2. Hwa-Ping Feng
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  3. Craig R. Shadle
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  4. Terry O’Reilly
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  5. John A. Wagner
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  6. Joan R. Butterton
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Corresponding author

Correspondence to Joan R. Butterton.

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Supplementary Table 1

Adverse events* (DOCX 38 kb)

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Lin, W.H., Feng, HP., Shadle, C.R. et al. Pharmacokinetic and pharmacodynamic interactions between the hepatitis C virus protease inhibitor, boceprevir, and the oral contraceptive ethinyl estradiol/norethindrone. Eur J Clin Pharmacol 70, 1107–1113 (2014). https://doi.org/10.1007/s00228-014-1711-0

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  • DOI: https://doi.org/10.1007/s00228-014-1711-0

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