An Integrated Population Pharmacokinetic Analysis to Characterize Levonorgestrel Pharmacokinetics After Different Administration Routes
An Integrated Population Pharmacokinetic Analysis to Characterize Levonorgestrel Pharmacokinetics After Different Administration Routes
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DOI：
10.1002/jcph.1288
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发表时间：
2018-12-01
影响因子：
2.9
通讯作者：
Garmann, Dirk
中科院分区：
文献类型：
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作者：
Reinecke, Isabel;Hofmann, Birte;Garmann, Dirk
为了比较不同给药途径下左炔诺孕酮的药代动力学（PK），进行了综合群体PK分析。该分析整合了来自10项临床药理学研究的数据，得到了一个单一的综合群体PK模型（及其应用）描述6种含左炔诺孕酮避孕药的左炔诺孕酮PK及其变异性：3种宫内系统（IUS;左炔诺孕酮[LNG]-IUS 20 [Mirena（（R））]、LNG-IUS 12 [Kyleena（（R））]和LNG-IUS 8 [Jaydess（（R））/Skyla（（R））]）; 2种口服避孕药（仅含孕激素的药丸[Microlut（（R））/Norgeston（（R））]和复方口服避孕药[Miranova（（R））]）;以及皮下植入剂（Jadelle（R）。含左炔诺孕酮的避孕药经口给药或作为埋植剂主要通过其全身（未结合）左炔诺孕酮暴露发挥作用，而通过IUS给药的左炔诺孕酮直接释放到子宫腔中，导致全身左炔诺孕酮浓度较低。综合群体PK分析显示，复方口服避孕药导致最高的左炔诺孕酮暴露，其次是仅孕激素药丸和植入剂，导致相似的左炔诺孕酮暴露，以及IUS，导致最低的左炔诺孕酮暴露（按降序排列：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）的指定使用持续时间结束时，差异更加明显。比较3种IUS和植入物，植入物的体内释放速率最高，其次是LNG-IUS 20，然后是LNG-IUS 12，LNG-IUS 8最低。这与左炔诺孕酮总浓度的比较一致。
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((R))], LNG-IUS 12 [Kyleena((R))], and LNG-IUS 8 [Jaydess((R))/Skyla((R))]); 2 oral contraceptives (the progestin-only pill [Microlut((R))/Norgeston((R))] and the combined oral contraceptive [Miranova((R))]); and a subdermal implant (Jadelle((R))). 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.