Pharmacokinetics and Pharmacodynamics of Tenofovir Reduced-Glycerin 1% Gel in the Rectal and Vaginal Compartments in Women: A Cross-Compartmental Study With Directly Observed Dosing
Jessica E Justman, Gonasagrie Lulu Nair, Craig W Hendrix, Jeanna M Piper, Mark A Marzinke, James Y Dai, Zhenyu Pan, Beth Galaska, Lisa Levy, Jill L Schwartz, Bhavna Balar, Ratiya P Kunjara Na Ayudhya, Ivy Mushamiri, Ian McGowan, Charlene S Dezzutti, MTN-014 Study Team, Jessica E Justman, Gonasagrie Lulu Nair, Craig W Hendrix, Jeanna M Piper, Mark A Marzinke, James Y Dai, Zhenyu Pan, Beth Galaska, Lisa Levy, Jill L Schwartz, Bhavna Balar, Ratiya P Kunjara Na Ayudhya, Ivy Mushamiri, Ian McGowan, Charlene S Dezzutti, MTN-014 Study Team
Abstract
Background: Evidence is lacking regarding whether vaginal pre-exposure prophylaxis with topical tenofovir (TFV) reduces the risk of rectal HIV acquisition.
Setting: Bronx, NY.
Methods: MTN-014 was a phase 1, cross-over, randomized sequence trial comparing the cross-compartment pharmacokinetics and pharmacodynamics of daily TFV reduced-glycerin 1% gel after 14 days each of rectal and vaginal application, with directly observed dosing and a 6-week washout period between phases.
Results: Fourteen HIV-uninfected women enrolled; 91% of doses were observed and 13 women completed all study procedures. TFV and TFV diphosphate (TFV-DP) were detected in most samples collected from the dosing compartment. After vaginal dosing, TFV was detected in 10/14 samples of rectal fluid (RF) (median 4.4 ng/sponge) and 1/13 rectal tissue samples (0.2 ng/mg); TFV-DP was detected in 2/13 rectal tissue samples at 59.8 and 76.5 fmol/mg. After rectal dosing, TFV was detected in 9/14 samples of vaginal fluid (median 1.1 ng/swab) and in 6/14 vaginal tissue samples (median below limit of quantification); TFV-DP was detected in 3/14 vaginal tissue samples at 17.3, 87.6, and 77.1 fmol/mg. Neither cervicovaginal lavage fluid nor RF collected 24 hours after rectal or vaginal dosing resulted in a statistically significant suppression of viral replication.
Conclusions: In this study of 14 days each of vaginal and rectal application of TFV reduced-glycerin 1% gel, we found only a small degree of cross-compartment distribution of TFV in RF and vaginal fluids and no pharmacodynamic activity in ex vivo testing. Although high TFV concentrations in the dosing compartment may be protective, low cross-compartment tissue concentrations are not likely to be protective.
Conflict of interest statement
Conflicts of Interest: The authors have no conflicts of interest to disclose.
Figures
Source: PubMed