The effect of rifampin on serum etonogestrel concentrations and biomarkers of ovulation among contraceptive implant users: a pharmacokinetic and pharmacodynamic study

by Selleckchem | Apr 27 2023

Objective: Rifampin, a strong CYP3A inducer, is the gold standard for evaluating CYP3A-mediated drug-drug interactions. We aimed to evaluate the pharmacokinetic and pharmacodynamic effects of a short course (2-weeks) of rifampin on serum etonogestrel (ENG) concentrations and serologic measures of ovarian activity (endogenous estradiol [E2] and progesterone [P4]) among ENG implant users.

Study design: We enrolled healthy females using ENG implants for 12-36 months. We measured baseline serum ENG concentrations using a validated liquid chromatography mass-spectrometry assay and baseline E2 and P4 concentrations using chemiluminescent immunoassays. After 2-weeks of rifampin 600mg daily, we repeated ENG, E2, and P4 measurements. We compared pre- and post-rifampin serum measurements using paired Wilcoxon signed-rank tests. We determined increased luteal activity as pre-exposure P4 <3.0ng/mL followed by post-rifampin P4 >3.0ng/mL with concurrent rise in post-treatment E2.

Results: Fifteen participants completed all study procedures. Participants' median age was 28.2 year (range 21.8-34.1), median body-mass index was 25.2kg/m2 (range 18.9-37.3), and median duration of implant use was 22 months (range 12-32). All participants experienced significant decreases from baseline ENG concentrations (median 164.0pg/mL [range 94.4-265.0]) to post-rifampin measurements (median 47.8pg/mL [range 24.7-82.8]) (p<0.001). Serum E2 concentrations also significantly increased with rifampin exposure (median 73pg/mL vs 202pg/mL, p=0.003); increases in serum P4 concentrations were not statistically significant (p=0.19). Three participants (20%) experienced increased luteal activity, with one presumptively ovulating post-rifampin (P4=15.8ng/mL).

Conclusion: With only short exposure to a strong CYP3A inducer, ENG implant users experienced clinically significant decreases in serum ENG concentrations that led to changes in biomarkers indicative of waning suppression of ovulation.

Comments：

The study aimed to evaluate the pharmacokinetic and pharmacodynamic effects of a short course (2-weeks) of rifampin on serum etonogestrel (ENG) concentrations and serologic measures of ovarian activity (endogenous estradiol [E2] and progesterone [P4]) among ENG implant users. The study enrolled healthy females using ENG implants for 12-36 months. The results showed that all participants experienced significant decreases in serum ENG concentrations and significant increases in serum E2 concentrations with rifampin exposure. Increases in serum P4 concentrations were not statistically significant. Three participants (20%) experienced increased luteal activity, with one presumptively ovulating post-rifampin (P4=15.8ng/mL). These findings suggest that even short-term exposure to a strong CYP3A inducer like rifampin can lead to clinically significant decreases in serum ENG concentrations and changes in biomarkers indicative of waning suppression of ovulation in ENG implant users.