Pharmacology of HIV integrase inhibitors

Abstract

Purpose of Review The purpose of this paper is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir and elvitegravir (both in Phase III drug development). Recent Findings Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter- and intra-patient pharmacokinetic variability is high. Twice daily 400mg dosing has been shown to be clinically superior to 800mg once daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was FDA approved in December 2011. Cobicistat-boosted elvitegravir, and the second generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, while boosted elvitegravir participates in additional CYP3A mediated interactions. Summary Raltegravir’s potent antiretroviral activity has resulted in widespread use in both treatment naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.

Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

“…Raltegravir is a preferred drug regimen used along with other ARVs for the treatment of HIV-1 infection in HIV-naive and -experienced patients (39). It is known that ARVs can be substrates, inhibitors, and/or inducers of drug efflux transporters, which can play an important role in ARV permeability in tissues having barrier functions, such as those in the blood-brain barrier, bloodtesticular barrier, and blood-intestinal barrier (3).…”

Clinical Pharmacology in HIV Therapy

“…This was followed by approval of the second generation INSTIs elvitegravir in 2012, dolutegravir in 2013, and most recently, bictegravir in 2018. They act by inhibiting viral DNA incorporation into the host genome (41).…”

Short Communication: Use of Raltegravir in Late-Presenting HIV-Infected Pregnant Women

“…The scarce evidence on these points for RGVcontaining regimens is still a limitation for its use, but the available information suggests it can be considered a safe and efficacious option for treating pregnant women. 19,21 In conclusion, in this case series, RGV-containing regimens were well tolerated and were associated with an impressive, rapid viral load decay of maternal VL at delivery, suggesting that RGV is a useful and safe ARV drug to reduce HIV-1 MTCT in late-presenting, HIV-infected pregnant women.…”

“…19 HIV-infected mothers are usually prescribed numerous medications for treatment/ prophylaxis. For this population, tolerability and a potential drug-drug interaction profile are important aspects to be considered when choosing an ARV regimen.…”