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.
Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA.
Contraception. 2019 Apr;99(4):256-263. doi: 10.1016/j.contraception.2018.12.009. Epub 2019 Jan 23.
The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women.
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 (K), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA).
Increasing of body habitus metrics is correlated with decreasing C (p<.0001) and AUC (p<.05) for both LNG and EE, but no correlation was found for C (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V, CLd and V 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.
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.
This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (C and AUC); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.
评估含左炔诺孕酮（LNG）的复方口服避孕药（COC）在肥胖女性中的药代动力学（PK）。
我们从四项临床研究中纳入了 89 名不同体重指数（BMI）类别的女性，对其数据进行了汇总和重新分析。采用零级吸收（K）、两室 PK 模型对 LNG 和炔雌醇（EE）的 PK 进行分析，以评估与一系列体重、BMI 和体表面积（BSA）相关的关键 PK 参数。
身体形态指标的增加与 LNG 和 EE 的 C（p<.0001）和 AUC（p<.05）降低相关，但 C 与体重无关（p≥.17）。体重和 BMI 的增加与清除率（CL）的适度增加（p≤.056）以及中央容积（V，p<.05）、分布清除率（CLd，p≤.001）和外周容积（V，p<.0001）的明显增加相关，LNG。对于 EE，随着体重、BMI 和 BSA 的增加，发现 CL 增加（p≤.009）。肥胖受试者的 V、CLd 和 V 值也增加（p<.0001）。LNG 和 EE 的半衰期和稳态容积在肥胖女性中更大（p<.0001）。
肥胖对 LNG 和 EE 的主要影响是 CL 适度增加和分布参数明显增加。我们没有观察到与肥胖相关的 LNG 和 EE 谷浓度差异。
这项人群 PK 分析表明，肥胖受试者对 LNG/EE 口服避孕药的系统暴露减少（C 和 AUC）；这些特定的差异不太可能降低肥胖女性正确使用 LNG 避孕药的避孕效果。
