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Title: Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers
Authors: Wang, L. 
Soon, G.H.
Seng, K.-Y.
Li, J.
Lee, E.
Yong, E.-L.
Goh, B.-C.
Flexner, C.
Lee, L.
Issue Date: Sep-2011
Citation: Wang, L., Soon, G.H., Seng, K.-Y., Li, J., Lee, E., Yong, E.-L., Goh, B.-C., Flexner, C., Lee, L. (2011-09). Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers. Antimicrobial Agents and Chemotherapy 55 (9) : 4090-4095. ScholarBank@NUS Repository.
Abstract: Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (Cmax), area under the concentration-time curve from 0 to 12 h (AUC0-12), and area under the concentration-time curve from 0 h to infinity (AUC0-∞) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir Cmax, AUC0-12, and AUC0-∞ were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs. Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Source Title: Antimicrobial Agents and Chemotherapy
ISSN: 00664804
DOI: 10.1128/AAC.00593-11
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