Single‐ and Multiple‐Dose Pharmacokinetics of Once‐Daily Formulations of Raltegravir

Abstract

A new once-daily formulation of raltegravir, an integrase strand transfer inhibitor indicated in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus-1 infection, is under development. Single-dose and steady-state pharmacokinetics of 1200 mg for 2 formulations of raltegravir were characterized in 2 open-label phase 1 studies in healthy male and female subjects aged 18 to 55 years. The new raltegravir 600-mg formulation had a higher relative bioavailability compared with the 400-mg tablets. Once absorbed, both 3 × 400-mg and 2 × 600-mg dosage forms of raltegravir exhibited similar systemic pharmacokinetics; in dictating bioavailability, differences were from increased absorption that was the result of improved in vivo disintegration/dissolution. Food had a smaller effect on the pharmacokinetics of raltegravir when given as 2 × 600-mg formulation (42% vs 73% decrease in AUC ). Steady state was generally reached in 2 days, with little to no accumulation with multiple-dose administration. Raltegravir 1200 mg was found to exhibit pharmacokinetic properties amenable for once-daily dosing and was generally well tolerated in healthy subjects after single and multiple doses. The new formulation improved the bioavailability of this Biopharmaceutics Classification System class II compound.

Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy: Mechanisms, Clinical Implications and Knowledge Gaps

“…The pharmacokinetics of the novel 1200 mg once-daily regimen (two new 600 mg tablets) in pregnant women are unknown. Raltegravir C trough of the 1200 mg once daily regimen were 38% lower compared with C trough of the 400 mg twice-daily regimen in healthy volunteers [ 47 ]. Consequently, it is relevant to study whether this new once-daily regimen will lead to C trough above the target of 0.02 mg/L [ 45 ] during pregnancy.…”

Effect of a High‐Fat Meal on the Pharmacokinetics of the HIV Integrase Inhibitor Cabotegravir

“…Previous studies have investigated the effect of the fat content of a meal on the level of drug exposure of integrase inhibitors . Raltegravir has been shown to exhibit considerable PK variability when it is administered with meals containing differing amounts of fat .…”

“…15,16 Raltegravir has been shown to exhibit considerable PK variability when it is administered with meals containing differing amounts of fat. 15,16 Raltegravir AUC from time 0 to 12 hours and C max were increased 2-fold following coadministration of raltegravir 400 mg twice daily with a high-fat meal. 15 Raltegravir AUC from time 0 to last observation following raltegravir 1200 mg (2 × 600 mg) once daily was increased 1.9% when the drug was administered following a high-fat meal but was decreased 42% when administered following a low-fat meal.…”

“…Previous studies have investigated the effect of the fat content of a meal on the level of drug exposure of integrase inhibitors . Raltegravir has been shown to exhibit considerable PK variability when it is administered with meals containing differing amounts of fat . Raltegravir AUC from time 0 to 12 hours and C max were increased 2‐fold following coadministration of raltegravir 400 mg twice daily with a high‐fat meal .…”

An HIV-infected Patient with No Serious Adverse Events after Overdosing on Raltegravir

“…Raltegravir is recognized as having few side effects, including a low rate of psychiatric symptoms, and showing few interactions with psychiatric drugs (3). It also offers a wide safety margin in terms of the plasma concentration, and the usefulness of high-dose once-daily oral administration has been described in some recent reports (7).…”