A Multi-Compartment, Single and Multiple Dose Pharmacokinetic Study of the Vaginal Candidate Microbicide 1% Tenofovir Gel
Public Deposited- Creator
- Schwartz, Jill L.
- Rountree, Wes
- Kashuba, Angela D. M.
- Brache, Vivian
- Creinin, Mitchell D.
- Poindexter, Alfred
- Kearney, Brian P.
- Abstract
- BackgroundTenofovir (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 FindingsForty-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 Cmax 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 1.2×104 to 9.9×106 ng/mL and 2.1×102 to 1.4×106 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 7.1×103 to 8.8×106 ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×102 to 3.5×104 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.ConclusionsSingle-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 registrationClinicalTrials.gov NCT00561496
- Date of publication
- 2011
- Keyword
- Antivirals
- Urology
- Infectious Diseases
- HIV
- Clinical Research Design
- Virology
- Clinical Trials
- Genitourinary Infections
- Biology
- Research Article
- Pharmacokinetics
- Infectious Disease Control
- Obstetrics and Gynecology
- Microbial Control
- HIV prevention
- Medicine
- Drugs and Devices
- Viral Diseases
- Microbiology
- Sexually Transmitted Diseases
- Clinical Pharmacology
- DOI
- Identifier
- PMID: 22039430
- PMCID: PMC3198383
- Onescience id: 60d3e4df30cbbf8341185a45b2eaf19195621639
- Publisher DOI: https://doi.org/10.1371/journal.pone.0025974
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- PloS One
- Journal volume
- 6
- Journal issue
- 10
- Page start
- e25974
- Language
- English
- ISSN
- 1932-6203
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