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

Schwartz JL, Rountree W, Kashuba AD, Brache V, Creinin MD, Poindexter A, Kearney BP - PLoS ONE (2011)

Bottom Line: 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.AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID.These results support further study of TFV gel for HIV prevention.

View Article: PubMed Central - PubMed

Affiliation: CONRAD, Eastern Virginia Medical School, Arlington, Virginia, United States of America. jschwartz@conrad.org

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.

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Related in: MedlinePlus

Tenofovir-diphosphate (TFV-DP) median concentrations in endocervical cells (ECC) and vaginal tissue after once- or twice-daily dosing.
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pone-0025974-g003: Tenofovir-diphosphate (TFV-DP) median concentrations in endocervical cells (ECC) and vaginal tissue after once- or twice-daily dosing.

Mentions: In those with detectable values, the vaginal biopsy concentrations of TFV-DP ranged from 1.8×102 to 3.5×104 ng/mL. The median Cmax after a single dose was 3.8×103 ng/mL (1.7×103 fmol/0.2 µL) (Table 3), and at the end of the 2-week phase was 3.1×103 ng/mL (1.3×103 fmol/0.2 µL) (Table 4) in those with detectable values. These latter Cmax median values were slightly different for the once-daily and the twice-daily groups (1.1×104 ng/mL [4.7×103 fmol/0.2 µL] compared to 0.3×104 ng/mL [1.2×103 fmol/0.2 µL], respectively) (Table S1) with once-daily concentrations higher at 8 hours and lower at 24 hours (Figure 3).


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

Schwartz JL, Rountree W, Kashuba AD, Brache V, Creinin MD, Poindexter A, Kearney BP - PLoS ONE (2011)

Tenofovir-diphosphate (TFV-DP) median concentrations in endocervical cells (ECC) and vaginal tissue after once- or twice-daily dosing.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198383&req=5

pone-0025974-g003: Tenofovir-diphosphate (TFV-DP) median concentrations in endocervical cells (ECC) and vaginal tissue after once- or twice-daily dosing.
Mentions: In those with detectable values, the vaginal biopsy concentrations of TFV-DP ranged from 1.8×102 to 3.5×104 ng/mL. The median Cmax after a single dose was 3.8×103 ng/mL (1.7×103 fmol/0.2 µL) (Table 3), and at the end of the 2-week phase was 3.1×103 ng/mL (1.3×103 fmol/0.2 µL) (Table 4) in those with detectable values. These latter Cmax median values were slightly different for the once-daily and the twice-daily groups (1.1×104 ng/mL [4.7×103 fmol/0.2 µL] compared to 0.3×104 ng/mL [1.2×103 fmol/0.2 µL], respectively) (Table S1) with once-daily concentrations higher at 8 hours and lower at 24 hours (Figure 3).

Bottom Line: 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.AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID.These results support further study of TFV gel for HIV prevention.

View Article: PubMed Central - PubMed

Affiliation: CONRAD, Eastern Virginia Medical School, Arlington, Virginia, United States of America. jschwartz@conrad.org

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.

Show MeSH
Related in: MedlinePlus