Comparative pharmacokinetic analysis of levonorgestrel-releasing intrauterine systems and levonorgestrel-containing contraceptives with oral or subdermal administration route

To compare systemic exposure to levonorgestrel (LNG) released from commercially available intrauterine systems (IUSs), a subdermal implant, and oral contraceptives. An integrated population pharmacokinetic (popPK) analysis of data from over 3400 individuals in ten clinical studies with six different LNG-releasing contraceptives (four long-acting reversible contraceptives [LARCs: LNG-IUS 8, 12, and 20, initially releasing LNG 14, 17.5, and 20 μg/day, a subdermal implant initially releasing LNG 100 μg/day according to label]; progestin-only pill [POP: LNG 30 μg/day]; and combined oral contraceptive [COC] pill [LNG 100 μg/day and ethinylestradiol 20 μg/day]), was conducted to generate a popPK model. LNG release rates, and total and unbound serum/plasma LNG concentrations with LARCs were estimated over the indicated period of use; maximum (C_max) and average (C_av) serum LNG concentrations were estimated at steady state for oral contraceptives. Influence of body weight on LNG PK was also investigated. Serum LNG concentration with LARCs increased with increasing daily LNG release rate, being lowest with LNG-IUS 8, higher with LNG-IUS 12 and LNG-IUS 20, and highest with the subdermal implant (1.7–2.1-times that with LNG-IUS 20). Compared with early serum LNG concentrations with LNG-IUS 20, C_av and C_max were 1.7- and 4.5-fold higher with POP, and 8.6- and 18-fold higher with COC. Total LNG bioavailability was >97% for the LNG-IUSs and 66–80% with other contraceptives. Serum/plasma LNG concentrations decreased with increasing body weight. Among the contraceptives examined, COC had the highest and LNG-IUSs the lowest systemic exposure to LNG. Systemic LNG concentration was inversely correlated to body weight.

为比较市售宫内给药系统（intrauterine systems, IUSs）、皮下埋植剂及口服避孕药所释放的左炔诺孕酮（levonorgestrel, LNG）的全身暴露量，本研究针对10项临床研究中超过3400名受试者的数据开展整合式群体药代动力学（population pharmacokinetic, popPK）分析。所纳入的6种不同左炔诺孕酮释放型避孕手段包括：4种长效可逆避孕药（long-acting reversible contraceptives, LARCs）——初始日释放左炔诺孕酮14μg、17.5μg、20μg的LNG-IUS 8、12、20型，以及按说明书初始日释放左炔诺孕酮100μg的皮下埋植剂；1种孕激素单方口服避孕药（progestin-only pill, POP）：日释放左炔诺孕酮30μg；以及1种复方口服避孕药（combined oral contraceptive, COC）：含左炔诺孕酮100μg与炔雌醇20μg。本研究最终构建了popPK模型，针对长效可逆避孕药，估算了其左炔诺孕酮释放速率，以及使用周期内血清/血浆中总左炔诺孕酮与游离左炔诺孕酮浓度；针对口服避孕药，则估算了其稳态下的血清左炔诺孕酮峰浓度（Cmax）与平均浓度（Cav）。本研究同时考察了体重对左炔诺孕酮药代动力学的影响。结果显示，长效可逆避孕药的血清左炔诺孕酮浓度随日释放速率升高而上升：LNG-IUS 8型浓度最低，LNG-IUS 12型与LNG-IUS 20型浓度更高，皮下埋植剂浓度最高，为LNG-IUS 20型的1.7~2.1倍。以LNG-IUS 20型的早期血清左炔诺孕酮浓度为参照，孕激素单方口服避孕药的Cav与Cmax分别为其1.7倍与4.5倍，复方口服避孕药的Cav与Cmax分别为其8.6倍与18倍。左炔诺孕酮宫内给药系统的左炔诺孕酮总生物利用度>97%，其余避孕手段的总生物利用度为66%~80%。血清/血浆左炔诺孕酮浓度随体重增加而降低。在所考察的避孕手段中，复方口服避孕药的左炔诺孕酮全身暴露量最高，左炔诺孕酮宫内给药系统最低。左炔诺孕酮的全身暴露浓度与体重呈负相关。