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

1 Center for HIV Prevention Research , UCLA AIDS Institute, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
AIDS research and human retroviruses (Impact Factor: 2.33). 09/2012; 28(11). DOI: 10.1089/AID.2012.0262
Source: PubMed


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.

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    • "Our findings indicate that reduced glycerin rectal tenofovir 1% gel affects expression of a different and much broader range of genes than N-9 2% gel, potentially affecting mucosal immune homeostasis, mitochondrial function, and regulation of epithelial cell differentiation and survival. These results make biological sense given that tenofovir is a DNA chain terminator, with possible off-target effects in human cells (Lewis et al., 2003), and that topical application achieves at least 100-fold higher active drug concentrations in the mucosa than oral administration of 300 mg tenofovir disoproxil fumarate (Anton et al., 2012; Hendrix et al., 2013). Moreover, tenofovir caused similar changes in primary vaginal epithelial cells cultured from several healthy women. "
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    • "In addition to its importance for vaccine studies, mucosal sampling is highly relevant in microbicide trials to understand how microbicides affect the mucosa [7]–[9] and to perform pharmacodynamic studies, such as determining ex vivo HIV infectivity of tissue from trial participants as a surrogate of product efficacy [10], [11]. Furthermore, mucosal sampling is integral to studies of the basic immunobiology of the FGT and of other sexually transmitted infections. "
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    • "To date, only one has demonstrated clinical efficacy, both against HIV and HSV-2 [80]: a vaginally applied 1% tenofovir gel, which was the first microbicide tested clinically that afforded study participants protection from viral transmission. While protection was only partial, CAPRISA004 served as the catalyst for further study on topical tenofovir gels, including those intended for rectal administration [81, 82]. While follow-up studies have failed to reproduce the partial protection observed in CAPRISA004 [83], post hoc data analysis suggests that this was due in large part to inadequate compliance of study subjects to the treatment regimen. "
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