Reformulated tenofovir gel for use as a dual compartment microbicide

Dezzutti, Charlene S.; Rohan, Lisa C.; Wang, Lin; Uranker, Kevin; Shetler, Cory; Cost, Marilyn; Lynam, J. D.; Friend, David R.

doi:10.1093/jac/dks173

Cited by 69 publications

(78 citation statements)

References 8 publications

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“…41 Overall, this study suggests that optimization of the vaginally formulated TFV 1% gel is needed for use as a rectal microbicide. 21 However, it is clear that rectal administration of an antiretroviral gel such as TFV is an extremely effective way to deliver high concentrations of active drug to highly vulnerable rectal mucosa. This study also demonstrates that intensified phase 1 trials including acceptability assessments, focused mucosal safety biomarkers, multicompartment PK, and ex vivo infectibility assays are feasible with high participant retention.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

131

176

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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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Section: Discussionmentioning

confidence: 99%

“…18 Despite this, there were no significant differences in genital tract adverse events (AEs) in clinical trials of this formulation. 14,19 However, given that hyperosmolar products can induce mucosal damage in the colon, 20,21 they require careful phase 1 evaluation if they are to be considered as candidate RMs.…”

mentioning

confidence: 99%

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

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

131

176

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“…154 The mucoadhesive polymers proposed in the literature and used 155 in commercial formulations for vaginal application are numerous. 156 Among the most common polyacrylic acid derivatives, such as carbomer…”

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confidence: 99%

Mucoadhesive and thermogelling systems for vaginal drug delivery

Caramella

Rossi

Ferrari

et al. 2015

Advanced Drug Delivery Reviews

211

148

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“…Development of these products requires optimization of formulations and safety studies related to topical application. This category includes tenofovir, which, in addition to ongoing studies with the original 1% gel formulation, is now being evaluated as a reduced glycerin gel formulation 15 that may be better tolerated, particularly when applied rectally. Other tenofovir formulations in development include a film, tablet, and intravaginal ring (IVR).…”

Section: Drugs For Topical Prepmentioning

confidence: 99%

A Perspective on Progress and Gaps in HIV Prevention Science

Kiser

Mesquita

Herold

2012

AIDS Research and Human Retroviruses

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In the past few years, the transdisciplinary field of HIV prevention has reached several milestones. Topically applied tenofovir gel provided significant protection from sexual transmission of HIV in a large-scale clinical trial and oral Truvada (emtricitabine/tenofovir disoproxil fumarate) was recently approved for preexposure prophylaxis (PrEP) following two successful clinical trials in men and women. These achievements are tempered by the disappointing results of other clinical trials, which highlight the complexities of prevention research. In this perspective, we discuss scientific and developmental gaps for topical chemoprophylaxis of the sexual transmission of HIV, which depends on the complex interactions between the pharmacokinetics and pharmacodynamics of drugs, formulation and delivery systems, anatomic site of transmission, and host mucosal immune defenses. Despite the considerable time and resources devoted to unraveling the initial steps in sexual transmission of HIV, current knowledge is based on animal models and human explanted tissue, which may not fully recapitulate what happens clinically. Understanding these events, including the role that sex hormones, semen, and mucosal secretions play in transmission, and the interplay between innate immunity, the mucosal environment, and drug efficacy is paramount. This drives some of the most pressing questions in the field.

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Reformulated tenofovir gel for use as a dual compartment microbicide

Abstract: Reducing the osmolality of the tenofovir gel resulted in improved epithelial integrity, which suggests better safety upon rectal use. The improved gel safety did not compromise drug release or anti-HIV-1 activity. These data support the use of this gel as a dual compartment microbicide.

Cited by 69 publications

References 8 publications

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

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

Mucoadhesive and thermogelling systems for vaginal drug delivery

A Perspective on Progress and Gaps in HIV Prevention Science

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