title: Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers.
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 (C(max)), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) 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 C(max), AUC(0-12), and AUC(0-∞) 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.
authors: Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456.
authors: Lingzhi
authors: L
authors: Wang
authors: Gaik Hong
authors: GH
authors: Soon
authors: Kok-Yong
authors: KY
authors: Seng
authors: Jun
authors: J
authors: Li
authors: Edmund
authors: E
authors: Lee
authors: Eu-Leong
authors: EL
authors: Yong
authors: Boon-Cher
authors: BC
authors: Goh
authors: Charles
authors: C
authors: Flexner
authors: Lawrence
authors: L
authors: Lee
mesh_terms: D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid; D019428:HIV Integrase Inhibitors / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium