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

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.

Conflict of interest statement

Competing Interests: Brian Kearney works for Gilead, Inc. which manufactures Vireadû. Jill Schwartz works for CONRAD, a nonprofit that supplies tenofovir gel. Alfred Poindexter is the Medical Director of Advances in Health, Inc. and has no competing interests. The declared affiliations do not alter the authors' adherence to PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Study procedures.

Figure 2. Participant flow diagram.

Figure 3. Tenofovir-diphosphate (TFV-DP) median concentrations in endocervical cells (ECC) and vaginal tissue after once- or twice-daily dosing.

Figure 4. Tenofovir (TFV) and tenofovir-diphosphate (TFV-DP) median concentrations in blood, cervicovaginal fluid and vaginal tissue following single and multiple doses.

For vaginal tissue measurements, 15/36 (42%) single dose data points and 16/45 (38%) multiple dose data points had TFV-DP concentrations above the limit of detection (4.5 fmol/0.2 µL). Figure 4B includes only data from subjects with detectable concentrations. PBMC data from Hawkins et al. .