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Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure

Patterson, Kristine B.a; Prince, Heather A.a; Stevens, Trentona; Shaheen, Nicholas J.a; Dellon, Evan S.a; Madanick, Ryan D.a; Jennings, Stevenb; Cohen, Myron S.a; Kashuba, Angela D.M.a,b

doi: 10.1097/QAD.0b013e32835f2b49
Clinical Science

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 400 mg 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/m2. After the first dose, area under the time-concentration curve (AUC)0-12h was highest in the terminal ileum (594 μg*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 μg*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 μg*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.

aUniversity of North Carolina Department of Medicine

bUniversity of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.

Correspondence to Kristine B. Patterson, MD, University of North Carolina at Chapel Hill, 130 Mason Farm Road, CB 7215, Chapel Hill, NC 27599-7215, USA. Tel: +1 919 843 2540; fax: +1 919 966 8928; e-mail:

Received 7 November, 2012

Revised 16 January, 2013

Accepted 18 January, 2013

© 2013 Lippincott Williams & Wilkins, Inc.