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

Abstract

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.