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.
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.
Authors: G Mardirossian; M Tagesson; P Blanco; L G Bouchet; M Stabin; H Yoriyaz; S Baza; M Ljungberg; S E Strand; A B Brill Journal: J Nucl Med Date: 1999-09 Impact factor: 10.057
Authors: D Finzi; J Blankson; J D Siliciano; J B Margolick; K Chadwick; T Pierson; K Smith; J Lisziewicz; F Lori; C Flexner; T C Quinn; R E Chaisson; E Rosenberg; B Walker; S Gange; J Gallant; R F Siliciano Journal: Nat Med Date: 1999-05 Impact factor: 53.440
Authors: Ginger Lehrman; Ian B Hogue; Sarah Palmer; Cheryl Jennings; Celsa A Spina; Ann Wiegand; Alan L Landay; Robert W Coombs; Douglas D Richman; John W Mellors; John M Coffin; Ronald J Bosch; David M Margolis Journal: Lancet Date: 2005 Aug 13-19 Impact factor: 79.321
Authors: D Finzi; M Hermankova; T Pierson; L M Carruth; C Buck; R E Chaisson; T C Quinn; K Chadwick; J Margolick; R Brookmeyer; J Gallant; M Markowitz; D D Ho; D D Richman; R F Siliciano Journal: Science Date: 1997-11-14 Impact factor: 47.728
Authors: F J Palella; K M Delaney; A C Moorman; M O Loveless; J Fuhrer; G A Satten; D J Aschman; S D Holmberg Journal: N Engl J Med Date: 1998-03-26 Impact factor: 91.245
Authors: Steven A Yukl; Sara Gianella; Elizabeth Sinclair; Lorrie Epling; Qingsheng Li; Lijie Duan; Alex L M Choi; Valerie Girling; Terence Ho; Peilin Li; Katsuya Fujimoto; Harry Lampiris; C Bradley Hare; Mark Pandori; Ashley T Haase; Huldrych F Günthard; Marek Fischer; Amandeep K Shergill; Kenneth McQuaid; Diane V Havlir; Joseph K Wong Journal: J Infect Dis Date: 2010-10-12 Impact factor: 5.226
Authors: R T Davey; D G Chaitt; J M Albert; S C Piscitelli; J A Kovacs; R E Walker; J Falloon; M A Polis; J A Metcalf; H Masur; R Dewar; M Baseler; G Fyfe; M A Giedlin; H C Lane Journal: J Infect Dis Date: 1999-04 Impact factor: 5.226
Authors: Netanya S Utay; Douglas W Kitch; Eunice Yeh; Carl J Fichtenbaum; Michael M Lederman; Jacob D Estes; Claire Deleage; Clara Magyar; Scott D Nelson; Karen L Klingman; Barbara Bastow; Amneris E Luque; Grace A McComsey; Daniel C Douek; Judith S Currier; Jordan E Lake Journal: J Infect Dis Date: 2018-05-05 Impact factor: 5.226
Authors: Theodoros Kelesidis; Thuy Tien T Tran; James H Stein; Todd T Brown; Carlee Moser; Heather J Ribaudo; Michael P Dube; Robert Murphy; Otto O Yang; Judith S Currier; Grace A McComsey Journal: Clin Infect Dis Date: 2015-04-22 Impact factor: 9.079
Authors: Mackenzie L Cottrell; Kristine B Patterson; Heather M A Prince; Amanda Jones; Nicole White; Ruili Wang; Angela D M Kashuba Journal: Antivir Ther Date: 2015-06-03
Authors: David R Bakal; Lara E Coelho; Paula M Luz; Jesse L Clark; Raquel B De Boni; Sandra W Cardoso; Valdilea G Veloso; Jordan E Lake; Beatriz Grinsztejn Journal: J Antimicrob Chemother Date: 2018-08-01 Impact factor: 5.790