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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

Study procedures.
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pone-0025974-g001: Study procedures.

Mentions: Each female volunteer participated in six visits over three menstrual cycles, received gynecological examinations and was tested for pregnancy at every visit. Figure 1 details the study procedures. At screening, volunteers were given information about the study and provided written informed consent. Baseline serum biochemistries and complete blood counts were collected, and testing for genital infections was performed. The enrollment visit was scheduled on menstrual cycle day 19–24. Eligible volunteers were enrolled and randomized to collection of endocervical cells (ECC), cervicovaginal aspirate and vaginal biopsies at one of seven time points [0.5, 1, 2, 4, 6, 8, and 24 hour(s)] post-dose for measurement of TFV concentration. A single dose of intravaginal TFV gel was applied at the study site. Blood samples were collected at all seven time points to assess systemic TFV exposure.


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)

Study procedures.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025974-g001: Study procedures.
Mentions: Each female volunteer participated in six visits over three menstrual cycles, received gynecological examinations and was tested for pregnancy at every visit. Figure 1 details the study procedures. At screening, volunteers were given information about the study and provided written informed consent. Baseline serum biochemistries and complete blood counts were collected, and testing for genital infections was performed. The enrollment visit was scheduled on menstrual cycle day 19–24. Eligible volunteers were enrolled and randomized to collection of endocervical cells (ECC), cervicovaginal aspirate and vaginal biopsies at one of seven time points [0.5, 1, 2, 4, 6, 8, and 24 hour(s)] post-dose for measurement of TFV concentration. A single dose of intravaginal TFV gel was applied at the study site. Blood samples were collected at all seven time points to assess systemic TFV exposure.

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