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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 (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. [10].
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pone-0025974-g004: 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. [10].

Mentions: Table S1 displays the median PK parameter estimates in the various anatomical compartments comparing the 4, 8 and 24 hour time points for single-dose and multiple-dose users. The AUC for vaginal tissue TFV-DP was two logs higher in multiple-dose compared to single-dose users but there were no noticeable differences between QD and BID. In women with detectable blood plasma concentrations, the median was close to zero at 24 hours. Vaginal tissue and endocervical cell TFV and TFV-DP concentrations remained high at 24 hours. The changes in TFV and TFV-DP concentrations in multiple compartments over the 24 hours following dose administration are shown in Figure 4. Figure 4B represents only those values with measurable concentrations of TFV-DP.


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 (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. [10].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025974-g004: 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. [10].
Mentions: Table S1 displays the median PK parameter estimates in the various anatomical compartments comparing the 4, 8 and 24 hour time points for single-dose and multiple-dose users. The AUC for vaginal tissue TFV-DP was two logs higher in multiple-dose compared to single-dose users but there were no noticeable differences between QD and BID. In women with detectable blood plasma concentrations, the median was close to zero at 24 hours. Vaginal tissue and endocervical cell TFV and TFV-DP concentrations remained high at 24 hours. The changes in TFV and TFV-DP concentrations in multiple compartments over the 24 hours following dose administration are shown in Figure 4. Figure 4B represents only those values with measurable concentrations of TFV-DP.

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