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Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy

European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy.

Methods

This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20–150 mg once daily) or sublingual buprenorphine/naloxone (8/2–24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2–7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7.

Results

Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC τ ) and maximum observed plasma (or serum) concentration (C max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC τ and C max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess.

Conclusions

There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.

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Fig. 1

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Acknowledgments

These data were presented at the 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 27–28 June 2012, Cambridge, MA. Bioanalytical support was provided by Bhavana Kantesaria, statistical support by Jianmin Zhao, and reporting support by Srinivas Annavarapu. All are employees of Merck Sharp & Dohme Corp. Medical writing and editorial assistance was provided by Tim Ibbotson, PhD, and Bianca B. Ruzicka, PhD, of ApotheCom. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ.

Conflict of interest

RD and LW have had a financial relationship with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, within the last 12 months that is relevant to this manuscript. H-PF, WL, FX, EO, JW, and JB are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ. EH is a former employee of Merck Sharp & Dohme, the Netherlands.

Author contributions

All authors reviewed the manuscript critically for important intellectual content and approved the final draft.

Funding

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

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Correspondence to Joan R. Butterton.

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Hulskotte, E.G.J., Bruce, R.D., Feng, HP. et al. Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy. Eur J Clin Pharmacol 71, 303–311 (2015). https://doi.org/10.1007/s00228-014-1789-4

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