Clinical Pharmacology Profile of Raltegravir, an HIV-1 Integrase Strand Transfer Inhibitor

Abstract

Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug-drug interactions and demonstrates a low propensity to be subject to drug-drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment.

Raltegravir Has a Low Propensity To Cause Clinical Drug Interactions through Inhibition of Major Drug Transporters: an In Vitro Evaluation

“…This suggests that RAL is not likely to be an inhibitor of either OATP1B1 or OATP1B3 in vivo (26)(27)(28). This in vitro observation is in line with clinical DDI studies showing that RAL did not cause clinically significant DDIs with pravastatin, a substrate of both OATP1B1 and OATP1B3 (22).…”

“…The lack of inhibition of OCT2 and MATEs by RAL at the clinically relevant exposure is consistent with the absence of an association between RAL administration and increases in serum creatinine. Inhibition of these renal transporters are the likely mechanism for increases in serum creatinine observed with some other antiretroviral drugs, including dolutegravir and cobicistat, and is a type of "drug interaction" that has been observed with cimetidine and trimethoprim (13,22). The inhibition of tubular creatinine secretion by dolutegravir, an inhibitor of OCT2, and cobicistat, an inhibitor of MATE1, leads to small elevations in serum creatinine that have not been associated with nephrotoxicity (39,40).…”

“…Using a Xenopus laevis oocyte system, RAL was found to be a substrate of the renal uptake transporter OAT1 (K m ϭ 150 M) (24), which is located in the basolateral membrane of the kidney proximal tubule and is involved in the renal excretion of many organic anions (41). Given that renal elimination of RAL is only a minor elimination pathway (9% of dose excreted unchanged into urine) (22) and transporter activity by OAT1 expressed as intrinsic clearance CL int (CL int ϭ V max /K m ϭ 0.2 l/oocyte/h) was ϳ25-fold lower than that for tenofovir (V max /K m ϭ 5.2 l/oocyte/h), a clinically relevant substrate of OAT1, RAL is not likely to exhibit altered pharmacokinetics when coadministered with an OAT1 inhibitor, such as tenofovir. In a clinical DDI study with tenofovir, RAL levels were slightly increased when coadministered with tenofovir but not to a clinically significant degree (37).…”

“…RAL is primarily eliminated via UGT1A1-mediated glucu-ronidation in humans (21). Thus, RAL has been shown both in vitro and in vivo to have a low propensity to be involved in CYPmediated DDIs as either a substrate or an inhibitor (22). Inhibition of UGT1A1 by atazanavir leads to slight increases in the plasma concentration of RAL.…”

Raltegravir Pharmacokinetics in Treatment-Naive Patients Is Not Influenced by Race: Results from the Raltegravir Early Therapy in African-Americans Living with HIV (REAL) Study

“…The pharmacological characteristics of RAL have been the focus of study following observations of considerable intra-and interindividual variability in the pharmacokinetic (PK) profile of the drug and a nonlinear relationship between RAL plasma concentrations and antiretroviral effect (17)(18)(19). Although the high variability in plasma concentrations of RAL relative to other antiretrovirals has complicated the modeling of RAL PK and therapeutic drug monitoring, the greater risk of treatment failure observed with once daily compared to twice daily RAL regimens suggests that drug exposure remains a critical determinant of the efficacy of this agent (20).…”