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

Objectives 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 to 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 600 mg daily, we repeated ENG, E2, and P4 measurements. We compared pre- and post-rifampin serum measurements using paired Wilcoxon signed-rank tests. Results Fifteen participants completed all study procedures. Participants' median age was 28.2 years (range 21.8–34.1), median body-mass index was 25.2 kg/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 164.0 pg/mL [range 94.4–265.0]) to post-rifampin measurements (median 47.8 pg/mL [range 24.7–82.8]) (p < 0.001). Serum E2 concentrations also significantly increased with rifampin exposure (median 73 pg/mL vs 202 pg/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 = 15.8 ng/mL). Conclusions 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. Implications Even a short, 2-week course of treatment with rifampin places etonogestrel contraceptive implant users at risk for decreased contraceptive efficacy. Clinicians should counsel patients using etonogestrel implants considering any duration of rifampin therapy on the need for backup nonhormonal contraception or the use of an intrauterine device to avoid unintended pregnancies.