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MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Hendrix, CW and Chen, BA and Guddera, V and Hoesley, C and Justman, J and Nakabiito, C and Salata, R and Soto-Torres, L and Patterson, K and Minnis, AM and Gandham, S and Gomez, K and Richardson, BA and Bumpus, NN (2013) MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments. PLoS ONE, 8 (1).

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Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: NCT00592124.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Hendrix, CW
Chen, BAbac12@pitt.eduBAC12
Guddera, V
Hoesley, C
Justman, J
Nakabiito, C
Salata, R
Soto-Torres, L
Patterson, K
Minnis, AM
Gandham, S
Gomez, K
Richardson, BA
Bumpus, NN
Date: 30 January 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 1
DOI or Unique Handle: 10.1371/journal.pone.0055013
Schools and Programs: School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
Other ID: NLM PMC3559346
PubMed Central ID: PMC3559346
PubMed ID: 23383037
Date Deposited: 08 Apr 2013 19:03
Last Modified: 27 Jun 2018 17:55


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