Prediction of drug pro-arrhythmic cardiotoxicity using a semi-physiologically based pharmacokinetic model linked to cardiac ionic currents inhibition

Drug-induced torsades de pointes (TdP) risks are responsible for the withdrawal of many drugs from the market. Nowadays, assessments of drug-induced TdP risks are mainly based on maximum effective free therapeutic plasma concentration (EFTPCmax) and cardiac ionic current inhibitions using the human ventricular myocytes model (Tor-ORd model). Myocytes are targets of drug-induced TdP. The TdP risks may be directly linked to myocyte drug concentrations. We aimed to develop a semi-physiologically based pharmacokinetic (Semi-PBPK) model linked to cardiac ionic current inhibition (pharmacodynamics, PD) (Semi-PBPK-PD) to simultaneously predict myocyte drug concentrations and their TdP risks in humans. Alterations in action potential duration (AAPD90) were simulated using the Tor-ORd model and ionic current inhibition parameters based on myocyte or plasma drug concentrations. The predicted AAPD90 values were translated into in vivo alterations in QT interval (AQTc) induced by moxifloxacin, dofetilide, or sotalol. Myocyte drug concentrations of moxifloxacin, dofetilide, and sotalol gave better predictions of AQTc than plasma. Following validating the developed semi-PBPK-PD model, TdP risks of 37 drugs were assessed using AAPD90 and early afterdepolarization occurrence, which were estimated based on 10 x EFTPCmax and 10 x EFTMCmax (maximum effective free therapeutic myocyte concentration). 10 x EFTMCmax gave more sensitive and accurate predictions of pro-arrhythmic cardiotoxicity and the predicted TdP risks were also closer to clinic practice than 10 x EFTPCmax. In conclusion, pharmaco-kinetics and TdP risks of 37 drugs were successfully predicted using the semi-PBPK-PD model. Myocyte drug concentrations gave better predictions of AQTc and TdP risks than plasma.

Automated summary

This study developed a semi-physiologically based pharmacokinetic-pharmacodynamic model to predict myocyte drug concentrations and TdP risks. Myocyte drug concentrations provided better predictions of AQTc and TdP risks compared to plasma concentrations.