Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

• Published in: Antimicrobial Agents and Chemotherapy Vol. 55; no. 9; pp. 4090 - 4095
• Main Authors: Wang, Lingzhi, Soon, Gaik Hong, Seng, Kok-Yong, Li, Jun, Lee, Edmund, Yong, Eu-Leong, Goh, Boon-Cher, Flexner, Charles, Lee, Lawrence
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.09.2011
• Subjects: Adult; Aged; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Biological and medical sciences; blood; blood plasma; Chromatography, Liquid; confidence interval; half life; HIV Integrase Inhibitors; HIV Integrase Inhibitors - blood; HIV Integrase Inhibitors - metabolism; HIV Integrase Inhibitors - pharmacokinetics; Humans; liquid chromatography; Male; mass spectrometry; Medical sciences; metabolism; Middle Aged; mononuclear leukocytes; patients; pharmacokinetics; Pharmacology. Drug treatments; Pyrrolidinones; Pyrrolidinones - blood; Pyrrolidinones - metabolism; Pyrrolidinones - pharmacokinetics; Raltegravir Potassium; Tandem Mass Spectrometry; volunteers; Young Adult; Human; Antiretroviral agent; Integrase inhibitor; Healthy subject; Antiviral; Intracellular; Pharmacokinetics; Modeling; Raltegravir
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.00593-11

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.