title: A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate.
abstract: This Phase 1, randomized, two-site (United States), double-blind, placebo-controlled study enrolled 18 sexually abstinent men and women. All received a single 300-mg dose of oral tenofovir disoproxil fumarate (TDF) and were then randomized 2:1 to receive single and then seven daily rectal exposures of vaginally-formulated tenofovir (TFV) 1% gel or a hydroxyethyl cellulose (HEC) placebo gel. Blood, colonic biopsies and rectal and vaginal mucosal fluids were collected after the single oral TDF, the single topical TFV gel dose, and after 7 days of topical TFV gel dosing for extracellular analysis of TFV and intracellular analysis of the active metabolite tenofovir diphosphate (TFVdp) in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMC), including CD4+ and CD4- cell subsets. With a single rectal dose, TFV plasma concentrations were 24–33 fold lower and half-life was 5 h shorter compared to a single oral dose (p = 0.02). TFVdp concentrations were also undetectable in PBMCs with rectal dosing. Rectal tissue exposure to both TFV and TFVdp was 2 to 4-log10 higher after a single rectal dose compared to a single oral dose, and after 7 daily doses, TFVdp accumulated 4.5 fold in tissue. TFVdp in rectal tissue homogenate was predictive (residual standard error, RSE = 0.47) of tissue MMC intracellular TFVdp concentration, with the CD4+ cells having a 2-fold higher TFVdp concentration than CD4- cells. TFV concentrations from rectal sponges was a modest surrogate indicator for both rectal tissue TFV and TFVdp (RSE = 0.67, 0.66, respectively) and plasma TFV (RSE = 0.38). TFV penetrates into the vaginal cavity after oral and rectal dosing, with rectal dosing leading to higher vaginal TFV concentrations (p<0.01). Trial registration: ClinicalTrials.gov NCT00984971.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, United States of America.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Yang
authors.affiliation: Departments of Medicine and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Hendrix
authors.affiliation: Departments of Medicine and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Namandje
authors.initials: N
authors.lastname: Bumpus
authors.affiliation: Center for HIV Prevention Research, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Elliott
authors.affiliation: Department of Biostatistics, UCLA School of Public Health, Los Angeles, California, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Tanner
authors.affiliation: CONRAD, Arlington, Virginia, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Mauck
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ross
authors.initials: R
authors.lastname: Cranston
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.affiliation: Alpha StatConsult LLC, Damascus, Maryland, United States of America.
authors.forename: Nicola
authors.initials: N
authors.lastname: Richardson-Harman
authors.affiliation: Center for HIV Prevention Research, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Anton
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, United States of America.
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000285:Administration, Rectal; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000068698:Tenofovir; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D063065:Organophosphonates; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; D000225:Adenine