Original articlePharmacokinetics of the 1.5 mg levonorgestrel emergency contraceptive in women with normal, obese and extremely obese body mass index☆,☆☆
Introduction
Obesity has been identified as a risk factor for emergency contraceptive (EC) failure. Pooled analyses of prior randomized controlled studies designed to assess levonorgestrel (LNG) efficacy have shown a decrease in efficacy of LNG-EC with increasing body weight and body mass index (BMI) [1], [2], [3]. Gemzell-Danielsson contended that there was no evidence to support the hypothesis of loss of EC efficacy in subjects with high BMI or bodyweights [4].
Two studies have examined the pharmacokinetics of 1.5 mg doses of LNG in relation to obesity. Praditpan et al. assessed the PK of 1.5 mg doses of LNG in 16 normal and 16 obese women and found that the Cmax and AUC of LNG were nearly half the normal values in the obese women [5]. Calculated values of free LNG were also lower. Edelman et al. found similar differences for Cmax in obesity, but a curtailed PK sampling over 2.5 h was performed and thus other PK parameters could not be calculated [6]. While the FDA has numerous Guidances that provide advice on performing PK and PD studies in subjects with altered physiology, there is no Guidance for obesity and thus no indication of what changes in PK and efficacy would be clinically important.
We assessed the pharmacokinetics of levonorgestrel (LNG) after 1.5 mg oral doses in women with normal, obese and extremely obese BMI using comprehensive pharmacometric methodology. The primary objective was to compare various exposure metrics and PK parameters of LNG in relation to BMI. Our hypothesis is obese BMI users of LNG-EC have PK profiles that are consistent with reduced plasma protein binding of LNG and that these alterations affect the primary mechanism of action of LNG-EC, which is inhibition of ovulation.
Section snippets
Study subjects
A prospective cohort study was conducted at the University of Southern California (USC) in Los Angeles, CA, from March 2013 to May 2016 after IRB approval with listing in ClinicalTrials.gov (NCT02104609). We enrolled English- and Spanish-speaking women aged 18–35 years with regular menstrual cycles (24–35 days) and with either normal (BMI 18.5–24.9 kg/m2), obese (BMI=30–39.9 kg/m2), or extremely obese (BMI≥40 kg/m2) BMIs. Women were excluded if they were seeking pregnancy, using hormonal
Results
The demographic characteristics of the participants are summarized in Table 1.
Fig. 1 provides the mean concentrations of total LNG versus time for the three groups of women who received 1.5 mg tablets. Serum LNG concentrations are consistently higher in the women of normal BMI and lowest in the extremely obese group. Absorption occurred rapidly producing a sharp peak at about 2 h followed by a biexponential decline with a long terminal half-life typically averaging 30 to 46 h over the 96-h
Discussion
Our study found serum concentration versus time profiles of total and bioavailable LNG with smaller Cmax and AUC values in women with BMI>30. However, the calculated free LNG Cmax and AUC were very close in the three groups. Interestingly, BMI did not impact the Tmax for total or free LNG. The larger Vss seen in the obese groups for both total and free LNG are consistent with the greater tissue mass for distribution of the drug. Accordingly, longer t1/2 and MRT values in these groups were
Acknowledgments
We wish to thank the University of Southern California Reproductive Research Clinic, Clinical Trials Unit and SC-CTSI project coordinators and staff, especially Angelica Mora, Blanca Ovalle and Emily Silverstein.
We thank Dr. Penina Segall-Gutierrez for her contribution to study design.
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Funding Source: The Society of Family Planning funded this project, and was not involved in the design, conduct, analysis, interpretation of results, writing of the report or decision to submit the article for publication. The project also received support from the Southern California Clinical and Translational Science Institute (NIH/NCRR/NCATS) Grant # UL1TR000130 and NIH Grant No. GM 24211.
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Financial Disclosures: Anita L. Nelson receives Grants/Research support through Agile Pharmaceutical, ContraMed, Estetra SPRL, Evofem Inc, FHI (MonaLisa), Merck; receives Honoraria and serves on Speakers Bureau for Allergan, Bayer, Merck; serves as a Consultant/Advisory Board member for Agile, AMAG Pharma, Bayer, ContraMed, Merck PharmaNest. William J. Jusko has been a recent consultant for Novartis, Boehringer Ingelheim, Reveragen, and Bayer Healthcare Products. Frank Z. Stanczyk serves as a consultant for Agile Therapeutics, TherapeuticsMD, Pantarhei Bioscience, and Mithra Pharmaceuticals.