Pharmacokinetic Enhancers in HIV Therapeutics

• Published in: Clinical pharmacokinetics Vol. 53; no. 10; pp. 865 - 872
• Main Authors: Larson, Kajal B., Wang, Kun, Delille, Cecile, Otofokun, Igho, Acosta, Edward P.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-10-2014; Adis International; Springer Nature B.V
• Subjects: Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Biological and medical sciences; Carbamates - administration & dosage; Carbamates - pharmacology; Cobicistat; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug Combinations; Drug Interactions; Drug Therapy, Combination; General pharmacology; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Internal Medicine; Leading Article; Medical sciences; Medicine; Medicine & Public Health; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Ritonavir - metabolism; Ritonavir - pharmacokinetics; Ritonavir - pharmacology; Thiazoles - administration & dosage; Thiazoles - pharmacology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Tenofovir; Saquinavir; Atazanavir; Ritonavir; Tenofovir Disoproxil Fumarate; Infection; Virus; Human; Immunopathology; Treatment; Viral disease; Retroviridae; AIDS; Human immunodeficiency virus; Pharmacokinetics; Immune deficiency; Lentivirus
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-014-0167-9

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.