Clinical use of cobicistat as a pharmacoenhancer of human immunodeficiency virus therapy

Abstract

The pharmacoenhancement of plasma concentrations of protease inhibitors by coadministration of so-called boosters has been an integral part of antiretroviral therapy for human immunodeficiency virus (HIV) for 1.5 decades. Nearly all HIV protease inhibitors are combined with low-dose ritonavir or cobicistat, which are able to effectively inhibit the cytochrome-mediated metabolism of HIV protease inhibitors in the liver and thus enhance the plasma concentration and prolong the dosing interval of the antiretrovirally active combination partners. Therapies created in this way are clinically effective regimens, being convenient for patients and showing a high genetic barrier to viral resistance. In addition to ritonavir, which has been in use since 1996, cobicistat, a new pharmacoenhancer, has been approved and is widely used now. The outstanding property of cobicistat is its cytochrome P450 3A-selective inhibition of hepatic metabolism of antiretroviral drugs, in contrast with ritonavir, which not only inhibits but also induces a number of cytochrome P450 enzymes, UDP-glucuronosyltransferase, P-glycoprotein, and other cellular transporters. This article reviews the current literature, and compares the pharmacokinetics, pharmacodynamics, and safety of both pharmacoenhancers and discusses the clinical utility of cobicistat in up-to-date and future HIV therapy.

Keywords: drug safety; fixed-dose combinations; human immunodeficiency virus; pharmacoenhancers.

Figure 1

Pathway of renal creatinine transport via efflux transporters SLC22A2 and SLC47A1 over the proximal tubular cell membranes from blood to urine. Abbreviations: ABC, ATP-binding cassette; SLC, solute carrier; Pgp, P-glycoprotein; ABCG2, breast cancer resistance protein; ABCC2, multidrug resistance protein; SLC47A1, multidrug and toxin extrusion protein 1; SLC47A2, multidrug and toxin extrusion protein 2; SLC22A4, organic cation/ergothioneine transporter 1; SLC22A5, organic cation/ergothioneine transporter 2; SLC22A2, organic cation transporter 2.