Zhang Xinghai, Wang Xuanxuan, Li Rui, Zhang Chenning, Du Jianmin, Zhao Hengli, Wen Qing
Department of Clinical Research Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China.
Clin Pharmacokinet. 2024 Sep;63(9):1357-1370. doi: 10.1007/s40262-024-01402-2. Epub 2024 Jul 26.
Endometriosis, a common and distressing gynecological condition, affects fertility and causes pain, is often managed with medications such as Elagolix. The present study aimed to construct a physiologically based pharmacokinetic (PBPK) model for elagolix to predict its pharmacokinetics in different populations, including those with special conditions, to enhance treatment strategies for endometriosis.
The PBPK model was optimized using observational data based on the oral administration of elagolix in a healthy Chinese population under fasting conditions. Model accuracy was further verified by comparing the predicted postprandial elagolix concentration data for healthy Chinese individuals with observed data and by comparing these values with the predicted values in a US population model with renal injury or following multiple-dose administration.
Elagolix pharmacokinetic (PK) profiles in the Chinese and American populations exhibited no differences that were attributable to ethnicity. The model predicted in vivo PK in adolescents aged 14-18 years, revealing no clinically significant differences in the effects of elagolix between adolescents and adults. In addition, no predicted PK differences in individuals with overweight were observed. However, notable variations emerged in those classified as obesity class 2 and above compared to healthy individuals.
Our study presents a novel PBPK model for elagolix in healthy Chinese women, addressing a clinical data gap for its use in adolescents and obese patients. By validating the model with real-world factors, including diet and renal impairment, we provide initial pharmacokinetic predictions for these populations, contributing to a more informed clinical approach.
子宫内膜异位症是一种常见且令人苦恼的妇科疾病，会影响生育并引发疼痛，通常使用如艾拉戈利克等药物进行治疗。本研究旨在构建一个基于生理的艾拉戈利克药代动力学（PBPK）模型，以预测其在不同人群（包括特殊情况人群）中的药代动力学，从而优化子宫内膜异位症的治疗策略。
基于禁食条件下健康中国人群口服艾拉戈利克的观察数据对PBPK模型进行优化。通过将健康中国个体餐后艾拉戈利克浓度的预测数据与观察数据进行比较，并将这些值与美国肾损伤人群模型或多剂量给药后的预测值进行比较，进一步验证模型的准确性。
中国和美国人群中艾拉戈利克的药代动力学（PK）特征未显示出因种族导致的差异。该模型预测了14 - 18岁青少年的体内PK情况，结果显示青少年与成年人之间艾拉戈利克的效果在临床上无显著差异。此外，未观察到超重个体的预测PK差异。然而，与健康个体相比，2级及以上肥胖个体出现了显著差异。
我们的研究提出了一种针对健康中国女性的新型艾拉戈利克PBPK模型，填补了其在青少年和肥胖患者中应用的临床数据空白。通过纳入饮食和肾功能损害等实际因素对模型进行验证，我们为这些人群提供了初步的药代动力学预测，有助于采取更明智的临床方法。
