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.

MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection

“…We have shown separately that seminal fluid does not impact the in vitro antiviral activity of MIV-150 in vaginal tissues (P. Barnable and N. Teleshova, unpublished data). Further supporting the potential predictive value of product testing in explants, the TFV gel inhibited HIV in the tissues (45,46) and was shown to reduce HIV incidence by 39% overall (47). TFV gel was not effective in the VOICE trial (48), possibly due to lack of adherence as determined by PK studies (7).…”

Mucosal effects of tenofovir 1% gel

“…http://dx.doi.org/10.1101/008607 doi: bioRxiv preprint first posted online Sep. 1, 2014; logical sense given that tenofovir is a DNA chain terminator, with possible off-target effects in human cells 35 , and that topical application achieves at least one hundred-fold higher active drug concentrations in the mucosa than oral administration of 300 mg tenofovir disoproxil fumarate 7,36 . Moreover, tenofovir caused similar changes in primary vaginal epithelial cells cultured from several healthy women.…”

Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques

“…In addition, a recent metaanalysis demonstrated that the estimated per-act human immunodeficiency (HIV) transmission risk (per 10,000 exposures) for RAI is 138, compared to 11, 8, and 4 for insertive anal intercourse, receptive penile-vaginal intercourse, and insertive penile-vaginal intercourse, respectively (10). The risk of HIV acquisition via unprotected RAI may be further exacerbated through the improper use of vaginal microbicide gels or high osmolality personal lubricants in the rectal compartment, which have been shown to cause cellular inflammation and epithelial damage (11)(12)(13)(14)(15)(16)(17)(18)(19). These studies collectively highlight a need for a microbicide formulation that is specifically designed for safe application in both the vaginal and rectal compartments and that may also serve as a lubricant.…”