期刊
AIDS
卷 27, 期 9, 页码 1413-1419出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e32835f2b49
关键词
gut-associated lymphoid tissue; HIV cure; latency; pharmacokinetics; raltegravir
资金
- National Institutes of Health [R37 DK49381, R34 AI087065, K23 AI773355, U01 AI095031, P30 AI50410, UL1 RR025747, U19 AI31496]
- Merck Investigator Initiated Research Program
Objective: To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gut-associated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies. Design: Open-label pharmacokinetic (PK) study. Methods: HIV-negative men received RAL 400mg twice daily for 7 days. Seven blood plasma specimens were collected over 12-h intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose and on day 7 [multiple dose (MD)]. RAL concentrations were measured by validated LC-MS assay with 1 ng/ml lower limit of detection. Data were analyzed by noncompartmental methods (WinNonlin 6). Tissue exposures are reported as composite medians and tissue density of 1.04 g/ml is assumed for comparisons. Results: Fourteen men completed evaluations. Median (range) age was 24 (19-49) years and BMI 25 (19-31) kg/m(2). After the first dose, area under the time-concentration curve (AUC)(0-12h) was highest in the terminal ileum (594 mu g*h/ml). Exposures were 160, 68 and 39-fold greater than blood plasma at the terminal ileum, splenic flexure and rectum, respectively. After multiple doses, exposure was highest at the splenic flexure (2240 mu g*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 mu g*h/ml). Following multiple doses, exposures were 160 to 650-fold greater than blood plasma throughout the colon. Conclusion: RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than blood plasma. RAL exposure in GI tissue remains higher than any antiretroviral investigated to date. These data suggest that RAL should result in full suppression of viral replication in GI tissue and GALT. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
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