title: RMP-02/MTN-006: A phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate.
abstract: This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use "if somewhat protective" was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C(max) 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK-PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.
authors.affiliation: Center for HIV Prevention Research , UCLA AIDS Institute, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. panton@mednet.ucla.edu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Anton
authors.forename: Ross D
authors.initials: RD
authors.lastname: Cranston
authors.forename: Angela
authors.initials: A
authors.lastname: Kashuba
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: Namandjé N
authors.initials: NN
authors.lastname: Bumpus
authors.forename: Nicola
authors.initials: N
authors.lastname: Richardson-Harman
authors.forename: Julie
authors.initials: J
authors.lastname: Elliott
authors.forename: Laura
authors.initials: L
authors.lastname: Janocko
authors.forename: Elena
authors.initials: E
authors.lastname: Khanukhova
authors.forename: Robert
authors.initials: R
authors.lastname: Dennis
authors.forename: William G
authors.initials: WG
authors.lastname: Cumberland
authors.forename: Chuan
authors.initials: C
authors.lastname: Ju
authors.forename: Alex
authors.initials: A
authors.lastname: Carballo-Diéguez
authors.forename: Christine
authors.initials: C
authors.lastname: Mauck
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000285:Administration, Rectal; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017060:Patient Satisfaction; D012007:Rectum / Q000187:drug effects* / Q000473:pathology; D000068698:Tenofovir; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; D000225:Adenine