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Clinical Pharmacokinetics and Pharmacodynamics of Etravirine

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Abstract

Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and α1-acid glycoprotein and shows a relatively long elimination half-life of 30–40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of etravirine.

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Acknowledgements

All authors are employees of Tibotec BVBA (Mechelen, Belgium) or Tibotec Inc., (Yardley, PA, USA). Funding of research mentioned in this manuscript has been provided by Tibotec Pharmaceuticals. The design and conduct of trials and the collection, management, analysis and interpretation of the data were performed under the supervision and final responsibility of Tibotec Pharmaceuticals. In addition, Tibotec Pharmaceuticals was involved in the preparation, review and approval of this manuscript. Drug interaction trials with tipranavir, elvitegravir, maraviroc and raltegravir were conducted in cooperation with Boehringer Ingelheim GmbH, Gilead Sciences, Inc., Pfizer Global Research and Development, and Merck & Co., Inc., respectively.

Substantial contribution to the results presented in this manuscript has been provided by all members of the TMC125 development teams.

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Authors and Affiliations

  1. Tibotec BVBA, Mechelen, Belgium

    Monika Schöller-Gyüre, Araz Raoof, Goedele De Smedt & Richard M. W. Hoetelmans

  2. Tibotec Inc., Yardley, Pennsylvania, USA

    Thomas N. Kakuda

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  1. Monika Schöller-Gyüre
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  2. Thomas N. Kakuda
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Correspondence to Monika Schöller-Gyüre.

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Schöller-Gyüre, M., Kakuda, T.N., Raoof, A. et al. Clinical Pharmacokinetics and Pharmacodynamics of Etravirine. Clin Pharmacokinet 48, 561–574 (2009). https://doi.org/10.2165/10895940-000000000-00000

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