Work

Bridging the Gap Between hiPSC-CMs Cardiotoxicity Assessment and Clinical LVEF Decline Risk: A Case Study of 21 Tyrosine Kinase Inhibitors

Year: 2025

Type: article

Abstract: Objectives: There is growing concern over tyrosine kinase inhibitor (TKI)-induced cardiotoxicity, particularly regarding left ventricular dysfunction and heart failure in clinical treatment. These adverse effects often lead to treatment discontinuation, severely impacting patient outcomes. Therefore, there is an urgent need for more precise risk assessment methods. This study aimed to assess the cardiotoxicity of TKIs, refine in vitro to in vivo extrapolation (IVIVE) methodologies to improve predictive accuracy, and identify critical in vitro parameters for assessment. Methods: By leveraging high-throughput cardiotoxicity screening with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a mechanism-based toxicodynamic (TD) model for TKIs was constructed. A QSP-PK-TD model was developed by integrating pharmacokinetic (PK) and quantitative systems pharmacology (QSP) models. This model incorporates critical drug exposure factors, such as plasma protein binding, tissue–plasma partitioning, and drug distribution heterogeneity to enhance extrapolation accuracy. Results: The QSP-PK-TD model validated the reliability of IVIVE and identified the area under the curve of drug effects on mitochondrial membrane potential (AEMMP) and cardiomyocyte contractility (AEAAC) as key in vitro parameters for assessing TKI-induced cardiotoxicity. Incorporating critical drug exposure factors obviously improved qualitative and quantitative extrapolation accuracy. Conclusions: This study established a framework for predicting in vivo cardiotoxicity from in vitro parameters, enabling efficient translation of preclinical data into clinical risk assessment. These findings provide valuable insights for drug development and regulatory decision-making, offering a powerful tool for evaluating TKI-induced cardiotoxicity.

Source: Pharmaceuticals

DOI: 10.3390/ph18040450

Authors: Zhijie Wan, Chenyu Wang, Shizheng Luo, Jinwei Zhu, Hua He, Kun Hao

Institutions: China Pharmaceutical University, State Key Laboratory of Natural Medicine

Language: English

Topic: Chemotherapy-induced cardiotoxicity and mitigation

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499