Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing

Abstract

Objective To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations. Study design Healthy, reproductive-age women with obese and normal BMIs received 1.5 mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2). Dosing occurred during the follicular phase. Total and free LNG PK parameters were obtained via serum samples through an indwelling catheter at 0, 0.5, 1, 1.5, 2, and 2.5 hours. The primary outcome was the difference in total and free LNG concentration maximum (Cmax) between ECx1 and ECx2 in the obese group. Results A total of 10 women enrolled and completed the study (normal BMI = 5, median 22.8 kg/m2, range 20.8–23.7; obese BMI = 5, 39.5 kg/m2, range 35.9–46.7). The total LNG Cmax for obese subjects following ECx1 (5.57±2.48 ng/mL) was significantly lower than the level observed in normal BMI women (10.30±2.47, p=0.027). Notably, ECx2 increased the Cmax significantly (10.52±2.76, p=0.002); approximating the level in normal BMI subjects receiving ECx1. Free LNG Cmax followed a similar pattern. Conclusion Obesity adversely impacts both the total and free Cmax levels of LNG EC and this likely explains its lack of efficacy in obese women. Doubling the dose appears to correct the obesity-related PK changes but additional research is needed to determine if this also improves EC effectiveness in obese women. Implications This study demonstrates that obesity interferes with the pharmacokinetics of LNG EC, and that doubling the dose may be an effective strategy to improve its efficacy in obese women.

FSRH Guideline (April 2019) Overweight, Obesity and Contraception

“…A study210 of the pharmacokinetics of LNG-EC in five women with obesity and five women without obesity demonstrates that obesity adversely impacts maximum serum concentrations of LNG. The authors postulate that this may explain a reduction in effectiveness of LNG-EC in women with obesity.…”

“…Studies testing the effectiveness of double-dose LNG-EC are in progress, but its effectiveness is unknown. However, 3 mg LNG-EC is well tolerated and pharmacokinetic data210 suggest its potential ability to prevent unintended pregnancy more effectively than 1.5 mg LNG-EC in women weighing >70 kg or with a BMI >26 kg/m 2 .…”

Current controversies with oral emergency contraception

“…More recently, a pooled analysis of randomised controlled trials of LNG conducted by WHO ( n = 6873) reported higher pregnancy rates among women with obesity compared with women of normal weight (although this was only statistically significant with regression analysis and adjustment for several factors) . There are also pharmacokinetic data indicating that LNG takes a longer time to achieve steady‐state levels in women with obesity compared with those of normal BMI, which can be overcome by doubling the dose of LNG . Conversely, the pharmacokinetics of UPA is not affected by obesity .…”

Clarification of contraceptive drug pharmacokinetics in obesity

“…Ellero et al [25] found very low levels of the mRNA for 20 xenobiotic-metabolizing CYP genes in subcutaneous and visceral white adipose tissue of women. It is thus of great interest that Edelman et al [26] examined the plasma concentrations of LNG during the first 2.5 h after giving 1.5 mg doses of LNG (Next Choice™; Activis) to 5 obese (BMI ≥30 kg/m 2 ) and 5 normal-weight women. They had also measured unbound LNG and SHBG concentrations.…”

“…Thus, SHBG binding of LNG and EE may have a protective role for some tissues. A recent publication in this journal [40] has largely endorsed the free drug hypothesis in arguing for the relevance of measurements of unbound LNG concentrations in obese women [26]. However, as reviewed by Smith et al [41], there are many exceptions to the application of the free hormone hypothesis.…”