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. 2018 May 1;78(1):82-92.
doi: 10.1097/QAI.0000000000001648.

Differences in Local and Systemic TFV PK Among Premenopausal Versus Postmenopausal Women Exposed to TFV 1% Vaginal Gel

Andrea Ries Thurman  1 , Neelima Chandra  1 , Nazita Yousefieh  1 , Thomas Kimble  1 , Sharon M Anderson  1 , Mackenzie Cottrell  2 , Craig Sykes  2 , Angela Kashuba  2 , Jill L Schwartz  1 , Gustavo F Doncel  1
Affiliations

Differences in Local and Systemic TFV PK Among Premenopausal Versus Postmenopausal Women Exposed to TFV 1% Vaginal Gel

Andrea Ries Thurman et al. J Acquir Immune Defic Syndr. .

Abstract

Objective: We describe and compare the local and systemic pharmacokinetics (PK) of tenofovir (TFV) and TFV-diphosphate (TFV-DP) in healthy premenopausal (PRE) and postmenopausal (POST) women using TFV 1% gel and correlate local PK with other mucosal end points.

Methods: PRE (n = 20) and POST (n = 17) women used 2 doses of TFV 1% vaginal gel, separated by 2 hours. Blood and cervicovaginal samples were obtained 3 and 23 hours after the second dose. PRE women used gel in the follicular and luteal phases of the menstrual cycle. POST women used gel at baseline and again after approximately 2 months of treatment with 0.01% vaginal estradiol (E2) cream.

Results: Median TFV concentrations in cervicovaginal aspirate (ng/mL) and vaginal tissue (ng/mg) were significantly higher in PRE (4.3E10, 49.8) versus POST women (2.6E10, 2.2). POST women had significantly higher median molecular ratios of TFV-DP to TFV (3.7%) compared with PRE (0.19%). After vaginal E2 treatment, the local and systemic PK end points in POST women were generally similar to PRE women (all P values > 0.05). Importantly, median vaginal tissue TFV-DP concentrations (fmol/mg) among PRE, POST, and POST women after E2 therapy were similar (292.5, 463.3, and 184.6, respectively). Vaginal tissue TFV concentrations were significantly positively correlated with vaginal epithelial thickness, whereas vaginal tissue TFV-DP concentrations were positively correlated with density of vaginal CD4 and CD8 immune cells.

Conclusions: The state of the cervicovaginal mucosa has a significant impact on local and systemic PK of a topically applied microbicide.

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Conflict of interest statement

The authors have no funding or conflicts of interest to disclose.

Figures

FIGURE 1.
FIGURE 1.
Heat map of simple linear correlations between vaginal tissue TFV and TFV-DP concentrations and the molecular ratio of TFV-DP to TFV with mucosal end points of all premenopausal and postmenopausal participants at all TFV gel use visits. EPI, epithelium; LP, lamina propria; R, Spearman correlation coefficient; CALCD4, CD3–CD8. Green indicates negative linear correlation, red indicates positive linear correlation, and yellow and orange indicate intermediates between negative and positive linear correlation. Bolded items indicate significant correlation (P value < 0.05).
FIGURE 2.
FIGURE 2.
A, MRP-2 transporters in Ectocervix of PRE LUT phase versus POST at baseline. B, MDR-1 transporters in Ectocervix of PRE luteal versus POST at baseline.
See this image and copyright information in PMC

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