Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users

Abstract

Background Pharmacokinetic (PK) parameters based on short sampling times (48 h or less) may contain inaccuracies due to their dependency on extrapolated values. This study was designed to measure PK parameters with greater accuracy in obese users of a low-dose oral contraceptive (OC), and to correlate drug levels with assessments of end-organ activity. Study design Obese (BMI ≥30 kg/m2), ovulatory, otherwise healthy, women (n = 32) received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) for two cycles. EE and LNG PK parameters were characterized for 168 h at the end of Cycle 1. During Cycle 2, biweekly outpatient visits were performed to assess cervical mucus, monitor ovarian activity with transvaginal ultrasound, and obtain serum samples to measure EE, LNG, estradiol (E2), and progesterone (P) levels. PK parameters were calculated and correlated with end-organ activity and compared against control samples obtained from normal and obese women sampled up to 48 h in a previous study. Standard determination of PK accuracy was performed; defined by the dependency on extrapolated values (‘excess’ area under the curve of 25% or less). Results The mean BMI was 39.4 kg/m2 (SD 6.6) with a range of 30–64 kg/m2. Key LNG PK parameters were as follows: clearance 0.52 L/h (SD 0.24), half-life 65 h (SD 40), AUC 232 h*ng/mL (SD 102) and time to reach steady-state 13.6 days (SD 8.4). The majority of subjects had increased ovarian activity with diameter of follicles ≥8 mm (n = 25) but only seven women had follicles ≥10 mm plus cervical mucus scores ≥5. Evidence of poor end-organ suppression did not correlate with the severity of the alterations in PK. As compared to historical normal and obese controls (48 h PK sampling), clearance, half-life, area under the curve (AUC) and time to reach steady-state were found to be significantly different (p ≤ 0.05) in obese women undergoing a longer duration of PK sampling (168 h). Longer sampling also improved PK accuracy for obese women (excess AUC 20%) as compared to both normal and obese controls undergoing shorter sampling times (48 h) with excess AUCs of 25% and 50%, respectively. Conclusions Obesity results in significant alterations in OC steroid PK parameters but the severity of these alterations did not correlate with end-organ suppression. A longer PK sampling interval (168 h vs. 48 h) improved the accuracy of PK testing.

An Ethinyl Estradiol-Levonorgestrel Containing Oral Contraceptive Does Not Alter Cytochrome P4502C9 In Vivo Activity

“…Both of these in vitro studies demonstrate that CYP2C9 inhibition occurs at a supra-micromolar concentration of ethinyl estradiol. The maximum plasma concentrations of ethinyl estradiol achieved by women in the current study were approximately 100 pg/ml (approximately 0.33 pM) (Edelman et al, 2013). Given the 10 6 -10 9 differential in the plasma concentrations and IC 50 , it is highly unlikely that ethinyl estradiol contributes to CYP2C9 variability among women who use OCs.…”

Contraception in the Setting of Obesity and Bariatric Surgery

“…For use as an EC agent, it is necessary for a single dose of LNG to provide a peak serum level suffi cient to inhibit the LH surge. The lower effi cacy of LNG in obese women as an EC may be related to these altered pharmacokinetics and an inability to reach adequate serum levels for ovulation inhibition with a single dose of LNG [ 71 ]. Pharmacokinetics of UPA or LNG EC in obese women have not been reported.…”

“…When taken between 72 and 120 h after unprotected intercourse, UPA prevented pregnancy more effectively than LNG ( p = 0.037) [ 115 , 116 ]. Overall, UPA appears to have 50 % greater effi cacy than LNG at pregnancy prevention based on a trial directly com-paring UPA to LNG [ 71 ]. In this section we review data on the effi cacy of LNG and UPA in obese women.…”

“…The greatest risk factor for failure of oral EC is body weight, followed by intercourse during the fertile time of the cycle, and repeat acts of unprotected intercourse within the same cycle [ 71 ]. Obese women have a three times greater risk of pregnancy following use of oral EC than normal weight women (OR, 3.60; 95 % CI, 1.96-6.53, p < 0.001).…”

“…Pharmacokinetics of LNG are altered in obese women using LNG-containing OCs, including alterations in clearance, a longer time to achieve steady state, and lower peak serum levels [ 71 ]. For use as an EC agent, it is necessary for a single dose of LNG to provide a peak serum level suffi cient to inhibit the LH surge.…”