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

Distorted body representations are robust to differences in experimental instructions

Several recent reports have shown that even healthy adults maintain highly distorted representations of the size and shape of their body. These distortions have been shown to be highly consistent across different study designs and dependent measures. However, previous studies have found that visual judgments of size can be modulated by the experimental instructions used, for example, by asking for judgments of the participant’s subjective experience of stimulus size (i.e., apparent instructions) versus judgments of actual stimulus properties (i.e., objective instructions). Previous studies investigating internal body representations have relied exclusively on ‘apparent’ instructions. Here, we investigated whether apparent versus objective instructions modulate findings of distorted body representations underlying position sense (Exp. 1), tactile distance perception (Exp. 2), as well as the conscious body image (Exp. 3). Our results replicate the characteristic distortions previously reported for each of these tasks and further show that these distortions are not affected by instruction type (i.e., apparent vs. objective). These results show that the distortions measured with these paradigms are robust to differences in instructions and do not reflect a dissociation between perception and belief

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

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

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

TFV Plasma Half-life is shorter (p = 0.02) during rectal administration.

<p>Plasma concentration-time profile is shown (median and interquartile range). Nominal time for single rectal dose was shifted right by 0.250 h and multiple rectal dose by 0.500 h for clarity. N = 18 for oral dose, 12 single rectal dose, 12 multiple rectal dose. (BLQ values are imputed as 0.01.)</p

Study Design.

<p>Study Design.</p

Rectal tissue exposure to TFV and TFVdp (median ± IQR) is higher during rectal dosing with multiple rectal dosing, resulting in accumulation of TFVdp.

<p>Each set of figures documents the 30 min drug quantification in the left-side graph and the 24 hr in the right side graph in rectal tissue biopsy homogenate (5A, 5B) and isolated mucosal mononuclear immune cells (MMC) (5C). Comparisons performed with paired Wilcoxon signed-rank test; only a subset of patients gave both C_{30 min} and C_{24 h} samples. Figure S5A  =  TFV_Tissue; Figure S5B  =  TFVdp_Tissue; Figure S5C  =  TFVdp_MMC. There is accumulation of TFV and TFVdp from multiple rectal dosing. Critical p for significance was 0.025 after Bonferroni correction.</p

Demographics.

<p>Demographics.</p