Safety, Tolerability, and Pharmacokinetics of Raltegravir After Single and Multiple Doses in Healthy Subjects

Abstract

Raltegravir is a novel human immunodeficiency virus-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration (IC95)=33 nM in 50% human serum). Three double-blind, randomized, placebo-controlled, pharmacokinetic, safety, and tolerability studies were conducted: (1) single-dose escalation study (10-1,600 mg), (2) multiple-dose escalation study (100-800 mg q12 h x 10 days), and (3) single-dose female study (400 mg). Raltegravir was rapidly absorbed with a terminal half-life (t1/2) approximately 7-12 h. Approximately 7-14% of raltegravir was excreted unchanged in urine. Area under the curve (AUC)(0-infinity) was similar between male and female subjects. After multiple-dose administration, steady state was achieved within 2 days; there was little to modest accumulation of raltegravir. Trough levels were >33 nM for dose levels of 100 mg and greater. Raltegravir is generally well tolerated at doses of up to 1,600 mg/day given for up to 10 days and exhibits a pharmacokinetic profile supportive of twice-daily dosing with multiple doses of 100 mg and greater achieving trough levels >33 nM.

Differentially Stimulated CD4+T Cells Display Altered Human Immunodeficiency Virus Infection Kinetics: Implications for the Efficacy of Antiviral Agents

“…The differences observed in HIV kinetics led us to examine the sensitivity of the above cell populations to antiretroviral drugs targeting the early stages in the viral life cycle. To address this, cells were treated with zidovudine (AZT) (10 M), efavirenz (EFV) (0.1 M) (4,23,33), or the integrase inhibitors 118-D-24 (80 M) (26) and raltegravir (50 nM), which was recently approved for clinical use (8)(9)(10), at various time points postinfection. The inhibition of viral replication was assessed by quantifying intracellular p24 Gag levels 48 h postinfection.…”

A Conventional LC-MS Method Developed for the Determination of Plasma Raltegravir Concentrations

“…These results indicate our newly developed method achieves the same level of reproducibility and accuracy as the LC-MS/MS method. As plasma concentrations of raltegravir are expected in the 0.01 to 4.71 mg/ml range when raltegravir is administered at single dose of 400 mg, [16][17][18] our method successfully covers this region with good precision and accuracy. Actually, the raltegravir concentration change was clearly demonstrated; it rose from 1.2 (0 h) to 5.2 mg/ml (1 h), then decreased to 1.5 mg/ml (6 h) when raltegravir was orally administered 400 mg twice daily in an HIV-1-infected patient.…”

“…When raltegravir is administered by a single 400 mg dose, plasma concentrations are expected in the 0.01 to 4.71 mg/ml range. [16][17][18] In this study, raltegravir concentrations at steady state following multiple-dose administration ranged from 1.2 to 5.2 mg/ml.…”

Raltegravir: The evidence of its therapeutic value in HIV-1 infection

“…Singledose escalation studies over a dose range of 10-1200 mg of raltegravir demonstrated approximately dose-proportional increases in AUC and plasma concentrations. 17 Raltegravir was rapidly absorbed, and time to peak plasma concentrations were between 0.5 to 1.3 h. A biphasic decline in plasma concentrations was observed with an apparent half-life of initial phase of 1 h and a terminal phase half-life of 7-12 h. Raltegravir dose of 200 mg or higher achieved C 12 h concentrations greater than the protein-adjusted IC 95 value of 33 nM. Key pharmacokinetic parameters of raltegravir at 200 and 400 mg doses are summarized in Table 2.…”