苍术（Thunb.）DC. 在晚期肝内胆管癌患者中的群体药代动力学/药效学模型：剂量预测。
Population-pharmacokinetic/pharmacodynamic model of atractylodes lancea (Thunb.) DC. administration in patients with advanced-stage intrahepatic cholangiocarcinoma: a dosage prediction.
机构信息
Centre of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), 99, moo 18, Phaholyothin Road, Klongneung sub-district, Klongluang district, Pathumthani, 12121, Thailand.
Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Klongluang, Pathumthani, 12120, Thailand.
出版信息
BMC Complement Med Ther. 2024 Nov 6;24(1):384. doi: 10.1186/s12906-024-04618-8.
BACKGROUND
A recent phase 2A clinical study of Atractylodes lancea (Thunb.) DC. (AL) in patients with advanced-stage intrahepatic cholangiocarcinoma (iCCA) demonstrated significant reduction of the risk of tumor progression and mortality with a dose ranging from 1,000 to 2,000 mg. The present study aimed to determine the potential dosage regimen of AL for further phase 2B clinical study.
METHODS
Plasma-concentration time profiles of total AL bioactivity and clinical efficacy in patients with advanced-stage iCCA were obtained from Phase 2 A study. The population pharmacokinetic (pop-PK) model was developed. The pop-PK model and Monte-Carlo (MC) simulation, in conjunction with maximum concentration of AL (C) as a cut-off criterion, was performed and validated with clinical data. The optimal model was used to simulate further dosage regimens and clinical efficacy of AL.
RESULTS
The pop-PK properties of total AL bioactivity were best described by a compartmental model with zero-order absorption (without delay) and linear clearance. None of the investigated covariates improved model accuracy.The developed pop-PK with MC simulations following once-daily dosing of 1,000 mg and 2,000 mg adequately predicted the clinical efficacy (tumor progression and mortality). The once-daily dose of 2,500 mg is recommended for further phase 2B clinical study due to its relatively high efficacy on tumor progression inhibition (73%) and mortality rate reduction (71%) without excessive number of the administered capsules (23 capsules) and low risk of toxicities (<5%).
CONCLUSIONS
The applied pop-PK model with MC simulation, along with the appropriate cut-off pharmacokinetic parameters, can be used as a potential tool for supporting dosage prediction and selection for clinical studies, and thus reducing the rate of drug development failures.
TRIAL REGISTRATION
www.thaiclinicaltrials.org , WHO ICTRP search, TCTR20210129007 , Registed 29 January 2021.
背景
最近一项苍术（Atractylodes lancea（Thunb.）DC.）在晚期肝内胆管癌（iCCA）患者中的 2A 期临床试验表明，剂量范围在 1000 至 2000mg 时，肿瘤进展和死亡率的风险显著降低。本研究旨在确定苍术进一步 2B 期临床试验的潜在剂量方案。
方法
从 2A 期研究中获得了晚期 iCCA 患者的总苍术生物活性的血浆浓度-时间曲线和临床疗效数据。建立了群体药代动力学（pop-PK）模型。结合最大浓度（C）作为截断标准，进行了 pop-PK 模型和蒙特卡罗（MC）模拟，并结合临床数据进行了验证。使用最优模型模拟了苍术的进一步剂量方案和临床疗效。
结果
总苍术生物活性的 pop-PK 特性最好通过零级吸收（无延迟）和线性清除的房室模型来描述。未发现任何研究的协变量能提高模型的准确性。基于每日一次 1000mg 和 2000mg 给药的开发后的 pop-PK 与 MC 模拟能够充分预测临床疗效（肿瘤进展和死亡率）。由于其对肿瘤进展抑制（73%）和死亡率降低（71%）具有较高的疗效，同时不增加给药胶囊的数量（23 粒）和降低毒性风险（<5%），因此建议每日一次 2500mg 剂量用于进一步的 2B 期临床试验。
结论
应用 pop-PK 模型与 MC 模拟，以及适当的药代动力学参数截断值，可以作为支持临床试验剂量预测和选择的潜在工具，从而降低药物开发失败的几率。
试验注册
www.thaiclinicaltrials.org，世界卫生组织 ICTRP 检索，TCTR20210129007，2021 年 1 月 29 日注册。
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