Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model

Area of Science:

• Cardiovascular pharmacology
• Stem cell biology
• Drug toxicology

Background:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) offer a promising in vitro model for assessing drug-induced cardiac liabilities.
• Existing preclinical models, such as hERG inhibition assays, have limitations in predicting clinical outcomes like Torsade de Pointes (TdP) and QT prolongation.

Purpose of the Study:

• To optimize a predictive algorithm using hiPS-CMs for improved cardiac safety screening in drug discovery.
• To evaluate the efficacy of hiPS-CMs in detecting drug-induced arrhythmia and QT prolongation compared to established methods.

Main Methods:

• Real-time cellular impedance measurements were used to monitor beat rhythm and rate changes in hiPS-CMs exposed to diverse drug compounds.
• Key metrics included arrhythmic beating (IB20) and beat rate reduction (BR20), along with predicted proarrhythmic scores (PPS-IB20, PPS-BR20).
• In vitro-in vivo concordance was assessed using a threshold of ≤ 10 μM and incorporating effective serum therapeutic concentrations (C eff).

Main Results:

• The human cardiomyocyte arrhythmic risk (hCAR) model demonstrated high in vitro-in vivo concordance for TdP prediction (82-83%) and non-TdP arrhythmia detection (91%).
• Beat rate reductions in hiPS-CMs showed strong concordance (86-87%) with clinical QT prolongation, outperforming hERG inhibition assays (80%).
• The hCAR assay distinguished cytotoxic arrhythmias and showed superior performance over existing preclinical tools for predicting cardiac safety liabilities.

Conclusions:

• hiPS-CMs provide a robust and predictive model for evaluating drug-induced cardiac arrhythmias and QT prolongation.
• The hCAR model enhances cardiac safety assessment, offering greater predictivity for torsadogenicity and QT prolongation than current standard assays.
• This hiPS-CM based system is a valuable tool for improving the cardiac safety evaluation of drug candidates during discovery toxicology.