Limits...
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.

Show MeSH

Related in: MedlinePlus

Participant flow diagram.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198383&req=5

pone-0025974-g002: Participant flow diagram.

Mentions: Recruitment for this study occurred from March 27, 2007 to January 9, 2008. The last study visit was on April 11, 2008. A total of 49 women met eligibility criteria and were enrolled (Figure 2). All 49 women received a single dose of TFV gel in the clinic, but two discontinued, one before and one after sample collection. Therefore, 47 participants proceeded to the MD phase and were randomized to once (QD) or twice daily (BID) dosing. Two of these 47 participants discontinued prior to gel application. A total of 975 doses were applied. Nine participants completed the 12-hour substudy and used a total of nine doses.


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)

Participant flow diagram.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025974-g002: Participant flow diagram.
Mentions: Recruitment for this study occurred from March 27, 2007 to January 9, 2008. The last study visit was on April 11, 2008. A total of 49 women met eligibility criteria and were enrolled (Figure 2). All 49 women received a single dose of TFV gel in the clinic, but two discontinued, one before and one after sample collection. Therefore, 47 participants proceeded to the MD phase and were randomized to once (QD) or twice daily (BID) dosing. Two of these 47 participants discontinued prior to gel application. A total of 975 doses were applied. Nine participants completed the 12-hour substudy and used a total of nine doses.

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