Aim: This study aimed to generate and validate computational populations of human ventricular cells representing infant (1‑12 months) and young adult (12‑16 years) age groups, and to evaluate their responses to drugs.
Methods: Using mRNA expression data of ion channels, we created 10,000 parameter combinations per age group based on the O'Hara‑Rudy model. Populations were filtered through 12 cellular electrophysiological biomarkers and then refined with 3D ventricular simulations to match age‑specific QT intervals from literature. Final populations of 300 profiles per age were obtained. We simulated the effects of nine drugs at 1 time, 5 times, and 10 times the effective free therapeutic plasma concentration (EFTPC).
Results: Infants showed a 23% longer action potential duration at 90% repolarization (APD90) than young adults (381 ms vs. 308 ms), together with higher amplitude and a more positive plateau phase. Quinidine and Ibutilide produced the greatest APD90 prolongation in both groups. Early afterdepolarizations (EADs) occurred in infants at 1× EFTPC of Quinidine, whereas young adults required 5× EFTPC to develop them. Infant population exhibited EADs with Quinidine, Ibutilide and Vandetanib. For young adult population, EADs were detected only with Ibutilide and Quinidine.
Conclusion: Our multi‑scale in silico populations successfully recapitulate known pediatric‑adult electrophysiological differences and reveal increased susceptibility of infants to drug‑induced arrhythmias. This platform offers a promising alternative to risky clinical trials for optimizing pediatric drug dosing.