title: Pharmacokinetic enhancers in HIV therapeutics.
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.
authors.affiliation: Division of Clinical Pharmacology, University of Alabama at Birmingham, School of Medicine, 1670 University Blvd, Volker Hall, Room 258, Birmingham, AL, 35294-0019, USA.
authors.forename: Kajal B
authors.initials: KB
authors.lastname: Larson
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Cecile
authors.initials: C
authors.lastname: Delille
authors.forename: Igho
authors.initials: I
authors.lastname: Otofokun
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D000069547:Cobicistat; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019438:Ritonavir / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D013844:Thiazoles; D000069547:Cobicistat; D019438:Ritonavir