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Pharmacokinetic Enhancers in HIV Therapeutics

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Abstract

Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

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Acknowledgments

This manuscript was written with support from grants UO1 AI068632 and UO1 AI068636. Kajal. B. Larson, Kun Wang, Cecile Delille, Igho Otofokun, and Edward P. Acosta have no conflicts of interest to declare.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, University of Alabama at Birmingham, School of Medicine, 1670 University Blvd, Volker Hall, Room 258, Birmingham, AL, 35294-0019, USA

    Kajal B. Larson, Kun Wang & Edward P. Acosta

  2. Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai, China

    Kun Wang

  3. Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA

    Cecile Delille & Igho Otofokun

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  1. Kajal B. Larson
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  2. Kun Wang
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Correspondence to Edward P. Acosta.

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Larson, K.B., Wang, K., Delille, C. et al. Pharmacokinetic Enhancers in HIV Therapeutics. Clin Pharmacokinet 53, 865–872 (2014). https://doi.org/10.1007/s40262-014-0167-9

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