Clinical Pharmacokinetic and Pharmacodynamic Profile of the HIV Integrase Inhibitor Elvitegravir

Abstract

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.

Characterization of Binding of Raltegravir to Plasma Proteins

“…No binding of RAL to AAG could be evidenced. These binding characteristics differ slightly from those of other available integrase inhibitors, such as elvitegravir, which was shown to be 99.4% bound to plasma protein, with preferential binding to albumin (12). The median unbound RAL C min on a b.i.d.…”

Divalent Metals and pH Alter Raltegravir Disposition In Vitro

“…Elvitegravir and dolutegravir exposure has been shown to be reduced when these drugs are taken with antacids containing magnesium and aluminum, with the reduction being less marked when the drug is taken 2 h before the antacid (19,21). In healthy subjects, elvitegravir and dolutegravir absorption has also been shown to be influenced by food according to fat content (26,9), and it is recommended that elvitegravir be taken with food (20). Interestingly, dolutegravir exposure has also been shown to be moderately reduced when the drug is taken with a multivitamin containing magnesium, calcium, iron, zinc, and copper (19).…”

Pharmacokinetics and Safety of Boosted Elvitegravir in Subjects with Hepatic Impairment

“…EVG is metabolized by CYP3A4 and secondarily by glucuronidation via uridine glucuronosyl transferase 1A1/3 (UGT1A1/3) (8). Once-daily coadministration of EVG with ritonavir (100 mg) (EVG/r) or cobicistat (150 mg) (COBI-boosted EVG [EVG/co]), both potent and irreversible mechanism-based inhibitors of CYP3A4, causes a substantial increase in EVG plasma exposure.…”

“…EVG and COBI undergo primarily hepatic biotransformation, with minimal renal elimination (COBI, ϳ8% of dose for COBI; EVG, none) and are highly protein bound (COBI, 97 to 98%; EVG, 98 to 99%) (8). These attributes render the potential for PK alterations in subjects with hepatic impairment.…”