Dandan Luo1, Carolyn L Westhoff2, Alison B Edelman3, Melissa Natavio4, Frank Z Stanczyk4, William J Jusko5. 1. Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA; Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA. 2. Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA. 3. Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239, USA. 4. Department of Obstetrics and Gynecology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA. 5. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA. Electronic address: wjjusko@buffalo.edu.
Abstract
OBJECTIVE: The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women. STUDY DESIGN: We pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K0), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA). RESULTS: Increasing of body habitus metrics is correlated with decreasing Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V1, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V2, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V1, CLd and V2 also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obese women (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly. CONCLUSIONS: The primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations. IMPLICATIONS: This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.
OBJECTIVE: The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obesewomen. STUDY DESIGN: We pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K0), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA). RESULTS: Increasing of body habitus metrics is correlated with decreasing Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V1, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V2, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V1, CLd and V2 also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obesewomen (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly. CONCLUSIONS: The primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations. IMPLICATIONS: This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obesewomen who are correctly using LNG-containing contraceptives.
Authors: Victoria L Holt; Delia Scholes; Kristine G Wicklund; Kara L Cushing-Haugen; Janet R Daling Journal: Obstet Gynecol Date: 2005-01 Impact factor: 7.661
Authors: Alison B Edelman; Ganesh Cherala; Steven W Blue; David W Erikson; Jeffrey T Jensen Journal: Contraception Date: 2016-03-18 Impact factor: 3.375