Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity

• Published in: Computer methods and programs in biomedicine 2023-12, Vol.242, p.107860-107860, Article 107860
• Main Authors: Llopis-Lorente, Jordi, Baroudi, Samuel, Koloskoff, Kévin, Mora, Maria Teresa, Basset, Matthieu, Romero, Lucía, Benito, Sylvain, Dayan, Frederic, Saiz, Javier, Trenor, Beatriz
• Format: Article
• Language: English
• Subjects: Cardiac safety; Pharmacokinetic modeling; Population of models; Sex-specific cardiotoxicity; Torsade de Pointes
• ISSN: 0169-2607; 1872-7565
• DOI: 10.1016/j.cmpb.2023.107860

•Novel PK/EP methodology enhances TdP-risk in diverse patient sub-populations.•Sex and renal function impact drug-induced TdP risk.•Women with impaired renal function show heightened susceptibility to TdP.•The proposed methodology can help determine maximum dose regimens. In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods. Pharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels. Fifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p