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

  • Patterson K
  • Prince H
  • Stevens T
 et al. 
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Objective—To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gutassociated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies. Design—Open-label pharmacokinetic study Methods—HIV-negative men received RAL 400 mg twice daily for 7 days. Seven blood plasma (BP) specimens were collected over 12-hr intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose (FD) 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) yrs and BMI 25 (19–31) kg/m2. After the FD, AUC-0-12h was highest in the terminal ileum (594 µg*h/mL). Exposures were 160, 68 and 39-fold greater than BP 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 160–650-fold greater than BP throughout the colon. Conclusions—RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than BP. RAL exposure in GI tissue remains higher than any ARV investigated to date. ©

Author-supplied keywords

  • Gut-associated lymphoid tissue
  • HIV cure
  • Latency
  • Pharmacokinetics
  • Raltegravir

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  • Kristine B. Patterson

  • Heather A. Prince

  • Trenton Stevens

  • Nicholas J. Shaheen

  • Evan S. Dellon

  • Ryan D. Madanick

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