{"title":"晚期肝内胆管癌患者服用白术的群体药代动力学/药效学模型：剂量预测","authors":"Teerachat Saeheng, Juntra Karbwang, Kesara Na-Bangchang","doi":"10.1186/s12906-024-04618-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sub>max</sub>) 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.</p><p><strong>Results: </strong>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%).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>www.thaiclinicaltrials.org , WHO ICTRP search, TCTR20210129007 , Registed 29 January 2021.</p>","PeriodicalId":9128,"journal":{"name":"BMC Complementary Medicine and Therapies","volume":"24 1","pages":"384"},"PeriodicalIF":3.3000,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542380/pdf/","citationCount":"0","resultStr":"{\"title\":\"Population-pharmacokinetic/pharmacodynamic model of atractylodes lancea (Thunb.) DC. administration in patients with advanced-stage intrahepatic cholangiocarcinoma: a dosage prediction.\",\"authors\":\"Teerachat Saeheng, Juntra Karbwang, Kesara Na-Bangchang\",\"doi\":\"10.1186/s12906-024-04618-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sub>max</sub>) 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.</p><p><strong>Results: </strong>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%).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>www.thaiclinicaltrials.org , WHO ICTRP search, TCTR20210129007 , Registed 29 January 2021.</p>\",\"PeriodicalId\":9128,\"journal\":{\"name\":\"BMC Complementary Medicine and Therapies\",\"volume\":\"24 1\",\"pages\":\"384\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-11-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542380/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BMC Complementary Medicine and Therapies\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12906-024-04618-8\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"INTEGRATIVE & COMPLEMENTARY MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMC Complementary Medicine and Therapies","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12906-024-04618-8","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INTEGRATIVE & COMPLEMENTARY MEDICINE","Score":null,"Total":0}
引用次数: 0
摘要
背景：白术（Tractylodes lancea (Thunb.) DC.(AL）治疗晚期肝内胆管癌（iCCA）患者的2A期临床研究显示，在1000至2000毫克的剂量范围内，白术可显著降低肿瘤进展的风险和死亡率。本研究旨在确定AL的潜在剂量方案，以便进一步开展2B期临床研究：方法：从2期A研究中获得晚期iCCA患者总AL生物活性的血浆浓度时间曲线和临床疗效。建立了群体药代动力学（pop-PK）模型。将 AL 的最大浓度（Cmax）作为临界标准，进行了 pop-PK 模型和蒙特卡罗（Monte-Carlo，MC）模拟，并与临床数据进行了验证。最佳模型用于模拟 AL 的进一步剂量方案和临床疗效：结果：一个零阶吸收（无延迟）和线性清除的分区模型对总 AL 生物活性的 pop-PK 特性进行了最佳描述。所研究的协变量均未提高模型的准确性。在每日一次给药 1,000 毫克和 2,000 毫克的情况下，所开发的 pop-PK 与 MC 模拟能充分预测临床疗效（肿瘤进展和死亡率）。由于每天一次的 2,500 毫克剂量在抑制肿瘤进展（73%）和降低死亡率（71%）方面具有相对较高的疗效，且无需服用过多胶囊（23 粒），毒性风险也较低（结论），因此建议进一步进行 2B 期临床研究：应用pop-PK模型与MC模拟，以及适当的临界药代动力学参数，可作为支持临床研究剂量预测和选择的潜在工具，从而降低药物开发的失败率。试验注册：www.thaiclinicaltrials.org , WHO ICTRP search, TCTR20210129007 , Registed 29 January 2021.
Population-pharmacokinetic/pharmacodynamic model of atractylodes lancea (Thunb.) DC. administration in patients with advanced-stage intrahepatic cholangiocarcinoma: a dosage prediction.
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 (Cmax) 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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
