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.

Trial registration: ClinicalTrials.gov NCT00984971.

Figures

FIG. 1.

Study flow diagram.

FIG. 2.

CONSORT (Consolidated Standards of Reporting Trials) enrollment summary. STI, sexually transmitted infection.

FIG. 3.

Pharmacokinetics (PK): Tenofovir (TFV) levels in plasma and tenofovir diphosphate (TFV-DP) level in rectal tissue over 24 h postexposure. (A) Plasma (TFV): The Tmax and subsequent decay for detection of plasma TFV after single oral, single/topical–rectal, and 7-day topical–rectal are shown. Single oral exposures peak later and, at 24 h, plasma concentrations are ∼98% higher than either of the topical rectal exposures. (B) Tissue (TFV-DP): Detectable concentrations of TFV-DP from homogenized tissue biopsies acquired within the first 24 h for the single oral, single topical/rectal exposures and 30 min after the last of the 7-day topical rectal exposures are shown. (C) Pharmacokinetic–pharmacodynamic (PK–PD) correlation of tissue TFV-DP concentration with ex vivo tissue infectibility: The linear correlation of tissue TFV-DP (log10 fmol/mg) and infectivity [defined by log10-transformed cumulative p24 (pg/ml) on day 14] is shown for subjects with detectable tissue TFV-DP after single oral (n=18; 5 time points sampled over 14 days postexposure*), single topical exposure (n=12, five time points sampled over 14 days postexposure*), and 7 days topical exposure (n=12, 30 min after final exposure) to tenofovir product. [*Oral exposure: 18 subjects at 30 min and 9 subjects (group A or B) at 1–3, 4–6, 7–9, and 10–12 days; single topical/rectal: 12 subjects at 30 min and 6 subjects (group A or B) at 1–3, 4–6, 7–9, and 10–12 days.]

FIG. 4.

Changes in ex vivo infectibility by HIVBaL 104 TCID50 of rectal biopsies following TVF exposure. Graphs document the changes in cumulative p24 from ex vivo tissue infectibility at V2 (all baseline; no product exposure) compared to the same subject's tissue samples collected/exposed ex vivo following product exposure. (A and B) Show changes following single-oral exposure. As there was no placebo group during the oral-exposure stage, results from 30 minutes (A) and 24 hours (B) post-exposure are shown to demonstrate absence of delayed suppressive effects due to a systemically-delivered oral drug (B). (C and D) Show results at baseline (each graph: left side) and 30 minutes after (each graph: right side) single topical exposure to TFV gel (C) compared to HEC placebo (D). (E and F) Show the same arrangement 30 minutes following 7-days topical exposure. The points for the same individual are linked by a solid line. The p-value of a paired test (Wilcoxon for A,B; t-test for C–F) is displayed within each plot; effect sizes are displayed under each plot and ANCOVAs, showing differences between TFV-exposed and placebo groups, after adjusting for baseline measurements, are placed between respective graphs.