title: Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study.
abstract: OBJECTIVE
  This study was designed to assess the dose-response relationship between tissue, blood, vaginal and rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and ex vivo rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and rectal administration of TFV 1% vaginally-formulated gel.
  
  
  METHODS
  Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females.
  
  
  METHODS
  Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 2∶1 to receive a single then seven-daily rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and ex vivo HIV-1 challenge.
  
  
  RESULTS
  There was a significant fit for the TFVdp dose-response model for rectal tissue (p = 0.0004), CD4+MMC (p<0.0001), CD4-MMC (p<0.0001), and TotalMMC (p<0.0001) compartments with r2 ranging 0.36-0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC50 of rectal tissue TFVdp predicted to be necessary to suppress HIV in rectal tissue. The EC50 for CD4+MMC was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided in-vivo doses predicted to provide for 50% efficacy in the ex vivo assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC90 biopsy efficacy for CD4-MMC, CD4+MMC and TotalMMC compartments.
  
  
  CONCLUSIONS
  The TFVdp MMC compartment (CD4+, CD4- and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression. ClinicalTrials.gov NCT00984971.
authors.affiliation: Alpha StatConsult, LLC, Damascus, MD, United States of America.
authors.forename: Nicola
authors.initials: N
authors.lastname: Richardson-Harman
authors.affiliation: Departments of Medicine and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.affiliation: Departments of Medicine and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Namandjé N
authors.initials: NN
authors.lastname: Bumpus
authors.affiliation: CONRAD, Arlington, VA, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Mauck
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Cranston
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Kuo
authors.initials: K
authors.lastname: Yang
authors.affiliation: Center for HIV Prevention Research, UCLA AIDS Institute, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Elliott
authors.affiliation: Center for HIV Prevention Research, UCLA AIDS Institute, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Tanner
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh Medical School, Pittsburgh, PA, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Kashuba
authors.affiliation: Center for HIV Prevention Research, UCLA AIDS Institute, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Anton
mesh_terms: D000284:Administration, Oral; D000285:Administration, Rectal; D000328:Adult; D001706:Biopsy; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005782:Gels; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D008297:Male; D012007:Rectum / Q000187:drug effects; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014622:Vaginal Creams, Foams, and Jellies / Q000737:chemistry; D055815:Young Adult
chemical_list: D005782:Gels; D014622:Vaginal Creams, Foams, and Jellies; D002482:Cellulose; C002283:hydroxyethylcellulose; D000068698:Tenofovir