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The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects

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Abstract

Background and Objective

Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co-administration of single and multiple doses of rifampin on doravirine pharmacokinetics.

Methods

In period 1 of this open-label, two-period, fixed-sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4–18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements.

Results

Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78–1.06) and 0.90 (0.80–1.01), respectively. Doravirine maximum plasma concentration increased when co-administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21–1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10–0.15), plasma concentration at 24 h post-dose: 0.03 (0.02–0.04), maximum plasma concentration: 0.43 (0.35–0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion.

Conclusions

Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co-administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy.

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Acknowledgements

Medical writing assistance was provided by Carole Evans, PhD, of Complete Medical Communications, Hackensack, NJ, USA. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.

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Authors and Affiliations

  1. Merck & Co., Inc., Kenilworth, NJ, USA

    Ka Lai Yee, Sauzanne G. Khalilieh, Rosa I. Sanchez, Rachael Liu, Matt S. Anderson & Joan R. Butterton

  2. Celerion, Lincoln, NE, USA

    Helen Manthos, Timothy Judge & John Brejda

  3. 770 Sumneytown Pike, WP75B-100, West Point, PA, 19486, USA

    Ka Lai Yee

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  1. Ka Lai Yee
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  2. Sauzanne G. Khalilieh
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  3. Rosa I. Sanchez
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Correspondence to Ka Lai Yee.

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Funding

This research was funded by Merck & Co., Inc., Kenilworth, NJ, USA.

Conflict of interest

Ka L. Yee, Sauzanne G. Khalilieh, Rosa I. Sanchez, Rachael Liu, Matt S. Anderson, and Joan R. Butterton are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. Helen Manthos, Timothy Judge, and John Brejda have no conflicts of interest to disclose.

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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.

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All subjects gave written informed consent to participate in the trials.

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Yee, K.L., Khalilieh, S.G., Sanchez, R.I. et al. The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects. Clin Drug Investig 37, 659–667 (2017). https://doi.org/10.1007/s40261-017-0513-4

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