RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

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) Cmax 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

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Study flow diagram.

<p>Paired measures from compartment concentrations (CC) and both CC and biopsy samples (*) taken at the bolded visits: V3 (Visit 3: ∼30 mins post single oral dose), V5 (1–6 days post V3 dose), V6 (7–9 days post V3 dose), V7 (∼30 mins post single topical dose), V9 (1–3 days post V7 dose), V10 (7–12 days post V7 does) and V12 (∼30 mins post 7^th daily dose) used in the dose-response analysis.</p

CONSORT flowchart.

<p>CONSORT flowchart.</p

Noncompartmental Pharmacokinetic Parameters (^*Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis; ^**Composite Profile).

<p>*Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis.</p><p>**Composite Profile.</p><p>Noncompartmental Pharmacokinetic Parameters (^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106196#nt101" target="_blank">*</a>}Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis; ^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106196#nt102" target="_blank">**</a>}Composite Profile).</p

TFVdp in rectal tissue homogenate is predictive of intracellular TFVdp concentration in isolated rectal mucosal mononuclear cells (MMCs), with higher levels of phosphorylation in the CD4+ T cells compared to CD4- T cells.

<p>Intracellular TFVdp concentration in isolated rectal mucosal mononuclear cells increases linearly as TFVdp concentration in rectal tissue homogenate increases. (p<0.001, robust RSE  = 0.46) There is higher phosphorylation of TFV in CD4+ cells, seen in its higher y-intercept. The lines are the mean rectal tissue MMC TFVdp concentration predictions from robust linear regression model; solid is CD4+, dashed is CD4-. Shaded regions are the 10–90% confidence intervals of the mean prediction.</p