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).
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 max 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 4 to 9.9×10 6 ng/mL and 2.1×10 2 to 1.4×10 6 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 3 to 8.8×10 6 ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×10 2 to 3.5×10 4 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.
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Details
| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Schwartz, JL | | | | | Rountree, W | | | | | Kashuba, ADM | | | | | Brache, V | | | | | Creinin, MD | | | | | Poindexter, A | | | | | Kearney, BP | | | |
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| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID |
|---|
| Editor | Ravel, Jacques | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
|
| 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: |
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: |
22 Jun 2021 10:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13987 |
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