What are the pharmacokinetics of protease inhibitors in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Protease inhibitors exhibit substantial interpatient and intrapatient variability in pharmacokinetics. [46] Significant first-pass metabolism by CYP3A4 and 3A5 and intestinal efflux by p-glycoprotein is observed. [46] With the exception of indinavir, protease inhibitors are highly protein-bound (97-99%), primarily to albumin and alpha1 acid glycoprotein. [8] Distribution into the CNS is limited. Protease inhibitors have relatively short serum half-lives, ranging from 1.5-2 hours for indinavir and 7 hours for atazanavir. [8]

Reliance on metabolism through CYP3A4 results in significant potential for drug-drug interactions with other medications cleared through this pathway (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). Interactions with medications cleared through other CYP450 isoenzymes and phase II pathways (e.g., uridine glucuronosyltransferases [UGT]) are possible, depending on the individual protease inhibitor. [8]

Low-dose ritonavir (100-200 mg) is frequently coadministered with other protease inhibitors to block intestinal and hepatic 3A metabolism. The addition of low-dose ritonavir improves pharmacokinetic variability, resulting in more consistent serum concentrations throughout the dosing interval and improved treatment response. [46]  Cobicistat is a newer agent that also blocks CYP3A metabolism and is used to enhance the pharmacokinetic profile of protease inhibitors.

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