Clinical Pharmacometrics, Bayer AB, Solna, Sweden, on behalf of Bayer AG, Berlin, Germany.
Clinical Pharmacokinetics, Bayer AG, Berlin, Germany.
J Clin Pharmacol. 2018 Dec;58(12):1639-1654. doi: 10.1002/jcph.1288. Epub 2018 Sep 12.
To compare the pharmacokinetics (PK) of the progestin levonorgestrel for various routes of administration, an integrated population PK analysis was performed. This analysis integrated data from 10 clinical pharmacology studies and resulted in a single, comprehensive population PK model (and its applications) describing the PK of levonorgestrel and its variability for 6 levonorgestrel-containing contraceptives: 3 intrauterine systems (IUSs; levonorgestrel [LNG]-IUS 20 [Mirena ], LNG-IUS 12 [Kyleena ], and LNG-IUS 8 [Jaydess /Skyla ]); 2 oral contraceptives (the progestin-only pill [Microlut /Norgeston ] and the combined oral contraceptive [Miranova ]); and a subdermal implant (Jadelle ). The levonorgestrel-containing contraceptives administered orally or as an implant act mainly via their systemic (unbound) levonorgestrel exposure, whereas levonorgestrel administered via an IUS is released directly into the uterine cavity, resulting in lower systemic levonorgestrel concentrations. The integrated population PK analysis revealed that the combined oral contraceptive led to the highest levonorgestrel exposure, followed by the progestin-only pill and the implant, which led to similar levonorgestrel exposure, and the IUSs, which led to the lowest levonorgestrel exposure (in decreasing order: LNG-IUS 20, LNG-IUS 12, and LNG-IUS 8). The difference was even more distinct at the end of the indicated duration of use of 3 years (LNG-IUS 8) and 5 years (LNG-IUS 20 and LNG-IUS 12). Comparing the 3 IUSs and the implant, in vivo release rates were highest for the implant, followed by LNG-IUS 20, then LNG-IUS 12, and were lowest for LNG-IUS 8. This is in line with the comparison of the total levonorgestrel concentrations.
为了比较不同给药途径的孕激素左炔诺孕酮的药代动力学（PK），进行了综合人群 PK 分析。该分析整合了来自 10 项临床药理学研究的数据，得出了一个单一的、综合的人群 PK 模型（及其应用），用于描述 6 种含有左炔诺孕酮的避孕药具的 PK 及其变异性：3 种宫内节育系统（IUS；左炔诺孕酮[LNG]-IUS 20[Mirena]、LNG-IUS 12[Kyleena]和 LNG-IUS 8[Jaydess/ Skyla]）；2 种口服避孕药（孕激素仅避孕药[Microlut/Norgeston]和复方口服避孕药[Miranova]）；以及一种皮下埋植剂（Jadelle）。口服或作为植入物给药的含有左炔诺孕酮的避孕药主要通过其全身（非结合）左炔诺孕酮暴露发挥作用，而通过 IUS 给药的左炔诺孕酮则直接释放到子宫腔中，导致全身左炔诺孕酮浓度较低。综合人群 PK 分析显示，复方口服避孕药导致的左炔诺孕酮暴露最高，其次是孕激素仅避孕药和植入物，导致的左炔诺孕酮暴露相似，而 IUS 导致的左炔诺孕酮暴露最低（按顺序递减：LNG-IUS 20、LNG-IUS 12 和 LNG-IUS 8）。在 3 年（LNG-IUS 8）和 5 年（LNG-IUS 20 和 LNG-IUS 12）的指定使用期限结束时，差异更为明显。与 3 种 IUS 和植入物相比，体内释放率以植入物最高，其次是 LNG-IUS 20，然后是 LNG-IUS 12，而 LNG-IUS 8 最低。这与总左炔诺孕酮浓度的比较一致。
