Bs-452759-3 a novel in silico pharmacokinetic/electrophysiological modeling framework to assess the influence of sex and renal status on drug-induced arrhythmogenicity

In silico methods can improve the prediction of drug-induced Torsade de Pointes (TdP) at early stages of drug development. However, most computational models typically do not consider inter-individual response variability due to demographic covariates (like sex) or physiologic ones (like renal function). Depending on the molecule considered, sex and renal function may significantly impact pharmacokinetic processes and/or electrophysiological properties implied in TdP risk assessment. Predicting effects in such sub-populations is of interest as these patients are often excluded from clinical trials. To study the differences in drug effects at the cellular level on populations of men and women with normal and impaired renal function using in silico methods. Pharmacokinetic models considering sex and renal function as covariates were developed leveraging data published in pharmacokinetic studies for 6 high TdP risk drugs and 9 intermediate TdP risk drugs. Electrophysiologically calibrated populations of models of 300 males and 300 females were built by modifying the endocardial action potential model published by O’hara and colleagues (2011) according to experimental gene expression levels of 12 ion channels. Drug effects were simulated with the simple pore block model. Action potential duration (APD) mean difference between male and female populations in control conditions was 24.9 ms (p<0.05), in accordance with the literature. Simulations of different patient groups predicted that women with impaired renal function were especially susceptible to drug-induced arrhythmias, while healthy men were less prone to undergo TdP. Differences between patient groups were more remarkable for the high TdP risk drugs. Individuals with impaired renal function that suffered hyperkaliemia (K+>7 mM) presented a smaller APD prolongation than models with normal potassium levels. The pharmacokinetic/electrophysiological models were used to assess the maximum safe dose for different groups. For example, when Dofetilide dose was reduced from 0.5 mg/12h to 0.125 mg/12h, the incidence of repolarization abnormalities in the female population with impaired renal function dropped from 10/300 to 0/300. This study proposes a new methodology to include sex and renal function effects on in silico drug simulations and highlights their impact on drug-induced TdP risk. The modeling framework presented here may also help determine the maximum dose regimen of a drug to assure TdP-related safety.