Supplementary Material for: An Integrated TK-TD Model for Evaluation of Radix Aconitikusnezoffii (RAK)

Objective: An integrated TK-TD model with indirect response to toxicity was established using ADAPT 5 to evaluate abnormal heart rate (HR) and QT interval changes caused by Radix Aconitikusnezoffii (RAK). Methods: Plasma samples were collected from male SD rats, which were divided into the blank and RAK groups. HR and QT interval indicators were recorded. Four alternative TK models were analyzed, and the best fitting model was determined. An indirect toxicodynamics model was selected, and the relationship of plasma concentration-time-toxicity was linked by Hill’s equation. Results: A 1-compartment linear first-order elimination kinetic model with the biophase model – an indirect toxic effect response model – best described the data. The high-dose QT interval was evaluated. Model simulation with the ML method showed that the fitting values of 0–15 h all fell within the confidence interval (95%). AMOS analysis showed that almost all the load factor of the variable was >0.7, and the χ2 value was 4.169 indicating a significant difference. Load factor (correlation coefficient) between the HR and QT intervals was −0.965, indicating negative correlation. Conclusions: The integrated TK-TD model with linear atrioventricular first-order elimination kinetics and indirect response represents a novel mathematical method to evaluate drug-induced changes in HR and QT.

研究目的：采用ADAPT 5软件构建带间接毒性响应的整合型药代动力学-药效动力学（TK-TD）模型，以评估川乌（Radix Aconitikusnezoffii, RAK）所致的异常心率（HR）及QT间期变化。
研究方法：采集雄性SD大鼠的血浆样本，将其分为空白组与川乌给药组（RAK组），记录心率与QT间期相关指标。分析4种备选药代动力学模型，确定最优拟合模型；选用间接毒效动力学模型，通过Hill方程关联血浆浓度-时间-毒性三者的关系。
研究结果：采用带生物相模型的一室线性一级消除动力学模型（即间接毒性响应模型）可最优拟合实验数据。针对高剂量组的QT间期进行评估，采用机器学习（ML）方法进行模型模拟的结果显示，0~15小时内的拟合值均落入95%置信区间内。AMOS分析结果表明，绝大多数变量的载荷因子均大于0.7，卡方（χ²）值为4.169，提示存在显著性差异；心率与QT间期之间的载荷因子（相关系数）为-0.965，表明二者呈负相关关系。
研究结论：本研究构建的整合型线性房室一级消除动力学间接响应TK-TD模型，为评估药物所致心率与QT间期变化提供了一种全新的数学分析方法。