Plasma and Intracellular (Peripheral Blood Mononuclear Cells) Pharmacokinetics of Once-Daily Raltegravir (800 Milligrams) in HIV-Infected Patients

Abstract

The aim of this study was to evaluate the plasma and intracellular pharmacokinetics of raltegravir in HIV-infected patients receiving once-daily raltegravir. Five HIV-infected patients on stable therapy with lopinavir-ritonavir monotherapy whose HIV-1 RNA load was <50 copies/ml were included in this open-label, pilot study. Raltegravir was added to the antiretroviral regimen at a dose of 800 mg once daily from days 0 to 10. On day 10, a full pharmacokinetic profile was obtained for each participant. Raltegravir concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were determined by high-performance liquid chromatography with a fluorescence detector and by liquid chromatography-tandem mass spectrometry (LC-MS/ MS), respectively. The values of the raltegravir pharmacokinetic parameters in plasma and PBMCs were calculated by noncompartmental analysis. Raltegravir was well tolerated, and all participants completed the study. No differences in the times to the maximum concentration of raltegravir in plasma or the raltegravir half-lives were observed between plasma and PBMCs. The geometric mean raltegravir maximum concentration, the concentration at the end of the dosing interval, and the area under the concentration-time curve during the dose interval in plasma versus PBMCs were 2,640 ng/ml (range, 887 to 10,605 ng/ml) versus 199 ng/ml (range, 82 to 857 ng/ml) (geometric mean ratio [GMR], 13.30; 95% confidence interval [CI], 3.11 to 56.89; P ‫؍‬ 0.003); 89 ng/ml (range, 51 to 200 ng/ml) versus 7 ng/ml (range, 2 to 15 ng/ml) (GMR, 13.21; 95% CI, 3.94 to 44.26; P ‫؍‬ 0.001); and 12,200 ng ⅐ h/ml (range, 5,152 to 30,130 ng ⅐ h/ml) versus 909 ng ⅐ h/ml (range, 499 to 2,189 ng ⅐ h/ml) (GMR, 13.43; 95% CI, 5.13 to 35.16; P < 0.001), respectively. Raltegravir does not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma. Despite once-daily dosing, mean raltegravir concentrations at the end of the dosing interval in plasma and PBMCs exceeded the reported protein-binding-adjusted 95% inhibitory concentration (IC 95 ) and IC 50 for wild-type viral strains, respectively.

Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages

“…Limitations on the concentration of drug that can be consistently maintained in macrophages could explain the different resistance patterns in these two cell types. In HIV-infected patients, the concentration of raltegravir in peripheral blood mononuclear cells is approximately 1/10 of that present in plasma (35), but there are no data available describing the relative intracellular concentrations of integrase inhibitors in T cells and macrophages. It therefore would be interesting to determine whether macrophages indeed contain lower levels of raltegravir than T cells, and if so whether macrophages inhibit the diffusion of raltegravir into cells, degrade the drug intracellularly, or export drug that has already entered the cell.…”

Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir in HIV-Positive and Healthy Individuals

“…However, the rather high intrapatient variability might limit its effectiveness. Based on some evidence about pharmacokinetic and pharmacodynamic relationships (12,14) and on the good correlation between RAL intracellular concentrations and plasma concentrations (16,28), there is a need to further explore the relationship between efficacy and pharmacokinetic exposure and the potential role of concentration monitoring. Better-standardized studies based upon more extensive sampling on a better-defined population would circumvent some of the limitations inherent to observational studies.…”

Comparative antiviral activity of integrase inhibitors in human monocyte-derived macrophages and lymphocytes

“…RAL is a new drug belonging to a new class of antiretrovirals (INIs), which has demonstrated an exquisite potency, a clean safety profile also at once-daily dosing of 800 mg/day, and to not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma (Goffinet et al, 2009;Moltó et al, 2011;Murray et al, 2007;Steigbigel et al, 2008;Summa et al, 2008).…”