Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California, United States of America.
Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
PLoS One. 2022 Dec 27;17(12):e0279640. doi: 10.1371/journal.pone.0279640. eCollection 2022.
This study employed population pharmacokinetic (popPK) models to predict levonorgestrel (LNG) and ethinyl estradiol (EE) exposure after dosing with the transdermal contraceptive TWIRLA® (LNG/EE TDS) as a 12-week extended regimen in a healthy female population.
PopPK models were developed using data from a previously published phase 1, open-label, randomized clinical trial, ATI-CL14 (NCT01243580), in 36 healthy individuals. Models used cycle 2 data from 18 individuals who received the LNG/EE TDS, delivering LNG 120 μg/day and EE 30 μg/day, followed by a 1-week TDS-free period. Noncompartmental PK analyses were performed on simulated concentration-time profiles of 12 consecutive weeks of LNG/EE TDS use.
The simulated concentration-time profiles and PK parameters for the simulated extended regimen indicated that predicted LNG and EE exposures at week 12 were similar to week 3 (predicted geometric mean EE area under the concentration-time curve from time 0 to 168 h [AUC0-168] on week 3 was 0.2% lower than week 12 and LNG AUC0-168 on week 3 was 0.9% lower than week 12), suggesting both were at steady state by week 3. Therefore, no notable accumulation beyond that at week 3 is predicted for LNG and EE following a 12-week extended regimen. The results are supported by the accumulation ratios based on maximum concentration and the area under the curve being similar at weeks 3 and 12 for LNG and EE.
These results indicate that a 12-week extended LNG/EE regimen would provide similar systemic hormonal exposure as that seen by week 3 in a standard 28-day regimen, without further hormonal accumulation. The data support the safe use of a non-daily, low-dose hormonal contraceptive in an extended regimen but should be confirmed in a clinical PK study.
本研究采用群体药代动力学（popPK）模型预测在健康女性人群中，以 12 周延长方案使用经皮避孕贴 TWIRLA®（LNG/EE TDS）后左炔诺孕酮（LNG）和炔雌醇（EE）的暴露情况。
使用先前发表的一项 I 期、开放标签、随机临床试验 ATI-CL14（NCT01243580）的数据，建立 popPK 模型，该试验共纳入 36 名健康个体。模型使用接受 LNG/EE TDS 治疗的 18 名个体的第 2 个周期数据，该 TDS 每天释放 LNG 120μg，EE 30μg，随后为 1 周 TDS 无药物暴露期。对 LNG/EE TDS 连续使用 12 周的模拟浓度-时间曲线进行非房室 PK 分析。
模拟延长方案的浓度-时间曲线和 PK 参数表明，第 12 周预测的 LNG 和 EE 暴露量与第 3 周相似（第 3 周预测的 EE 从 0 至 168 小时的浓度-时间曲线下面积（AUC0-168）比第 12 周低 0.2%，第 3 周 LNG 的 AUC0-168 比第 12 周低 0.9%），表明第 3 周时两者均达到稳态。因此，在延长 12 周方案后，预计 LNG 和 EE 不会出现第 3 周以后的明显蓄积。基于最大浓度的蓄积比和第 3 周和第 12 周时的 AUC 相似，结果得到支持。
这些结果表明，12 周延长 LNG/EE 方案与 28 天标准方案第 3 周相比，可提供相似的全身激素暴露，不会进一步增加激素蓄积。数据支持在延长方案中使用非每日、低剂量激素避孕药的安全性，但需要在临床 PK 研究中得到证实。
