In silico assessment of nifedipine effects on human heart cells: Pharmacokinetic-pharmacodynamic analyses at the population level

摘要

This study aimed to utilise the value of integrating in vitro data and physiologically based pharmacokinetic (PBPK) models to quantitatively estimate the impact on pharmacokinetics (PK) and pharmacodynamics (PD). The objective was to predict pharmacodynamics (electrocardiogram (ECG) parameters) of nifedipine (NIF) after an oral administration by simulation. The computational models were performed for human transmural ECGs to model drug-induced changes in QT interval as well as changes in T-wave morphology. The differences in QTc interval due to NIF in healthy volunteers both males and females were predicted by the Cardiac Safety Simulator, providing a mechanistic understanding of clinical observation. The simulation results showed that NIF significantly shortened the QTcF in a concentration-dependent manner compared with baseline (placebo) control. Comparison of the simulated QT interval of non-QT-prolonging drug (NIF) against the clinical observations proved the accuracy of the model based prediction.