Review Article

Clinical Pharmacokinetics

, Volume 50, Issue 4, pp 229-244

First online:

Clinical Pharmacokinetic and Pharmacodynamic Profile of the HIV Integrase Inhibitor Elvitegravir

  • Srinivasan RamanathanAffiliated withGilead Sciences, Inc. Email author 
  • , Anita A. MathiasAffiliated withGilead Sciences, Inc.
  • , Polina GermanAffiliated withGilead Sciences, Inc.
  • , Brian P. KearneyAffiliated withGilead Sciences, Inc.

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Elvitegravir is a potent, boosted, once-daily, HIV integrase inhibitor with antiviral activity against wild-type and drug-resistant strains of HIV. Because elvitegravir is metabolized primarily by cytochrome P450 (CYP) 3A enzymes, coadministration with a strong CYP3A inhibitor such as ritonavir or cobicistat (also known as GS-9350), an investigational pharmacoenhancer, substantially increases (boosts) elvitegravir plasma exposures and prolongs its elimination half-life to ∼9.5 hours, allowing once-daily administration of a low 150 mg dose. Boosting also results in low intra- and intersubject pharmacokinetic variability and high elvitegravir trough concentrations (∼6- to 10-fold above the concentration producing 95% inhibition of wild-type HIV-1 virus [IC95] of 45 ng/mL [protein binding-adjusted]), which is the pharmacokinetic parameter best associated with its antiviral activity.

Data from extensive evaluation of the potential for boosted elvitegravir to undergo drug-drug interactions with other antiretroviral agents or concomitant medications indicate the absence of clinically relevant interactions or the need for dose modification in several cases, except for dose reduction of elvitegravir from 150 to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir. Dose adjustments for maraviroc and rifabutin, when each is coadministered with boosted elvitegravir, are consistent with their observed interactions with other ritonavir-boosted agents. The presence of a strong CYP3A inhibitor such as ritonavir or cobicistat renders the potential for increase in systemic exposures of CYP3A substrates coadministered with boosted elvitegravir. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies, mechanistic and special population studies, that has allowed a thorough understanding of elvitegravir clinical pharmacokinetics and its impact on pharmacodynamics.