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A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel

Schwartz, JL and Rountree, W and Kashuba, ADM and Brache, V and Creinin, MD and Poindexter, A and Kearney, BP (2011) A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel. PLoS ONE, 6 (10).

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Abstract

Background: Tenofovir (TFV) gel is being evaluated as a microbicide with pericoital and daily regimens. To inhibit viral replication locally, an adequate concentration in the genital tract is critical. Methods and Findings: Forty-nine participants entered a two-phase study: single-dose (SD) and multi-dose (MD), were randomized to collection of genital tract samples (endocervical cells [ECC], cervicovaginal aspirate and vaginal biopsies) at one of seven time points [0.5, 1, 2, 4, 6, 8, or 24 hr(s)] post-dose following SD exposure of 4 mL 1% TFV gel and received a single dose. Forty-seven were randomized to once (QD) or twice daily (BID) dosing for 2 weeks and to collection of genital tract samples at 4, 8 or 24 hrs after the final dose, but two discontinued prior to gel application. Blood was collected during both phases at the seven times post-dose. TFV exposure was low in blood plasma for SD and MD; median C was 4.0 and 3.4 ng/mL, respectively (C≤29 ng/mL). TFV concentrations were high in aspirates and tissue after SD and MD, ranging from 1.2×10 to 9.9×10 ng/mL and 2.1×10 to 1.4×10 ng/mL, respectively, and did not noticeably differ between proximal and distal tissue. TFV diphosphate (TFV-DP), the intracellular active metabolite, was high in ECC, ranging from 7.1×10 to 8.8×10 ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×10 to 3.5×10 ng/mL. AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID. Conclusions: Single-dose and multiple-dose TFV gel exposure resulted in high genital tract concentrations for at least 24 hours post-dose with minimal systemic absorption. These results support further study of TFV gel for HIV prevention. Trial registration: ClinicalTrials.gov NCT00561496. © 2011 Schwartz et al. max 4 6 2 6 3 6 2 4


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Schwartz, JL
Rountree, W
Kashuba, ADM
Brache, V
Creinin, MD
Poindexter, A
Kearney, BP
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorRavel, JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 25 October 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0025974
Schools and Programs: Graduate School of Public Health > Epidemiology
School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
MeSH Headings: Adenine--administration & dosage; Adenine--analogs & derivatives; Adenine--blood; Adenine--pharmacokinetics; Administration, Topical; Adult; Female; Gels; Humans; Phosphonic Acids--administration & dosage; Phosphonic Acids--blood; Phosphonic Acids--pharmacokinetics; Reverse Transcriptase Inhibitors--administration & dosage; Reverse Transcriptase Inhibitors--blood; Reverse Transcriptase Inhibitors--pharmacokinetics; Vagina
Other ID: NLM PMC3198383
PubMed Central ID: PMC3198383
PubMed ID: 22039430
Date Deposited: 07 Sep 2012 20:57
Last Modified: 30 Mar 2021 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/13987

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