Effects of Serum and Compound Preparation Methods on Delayed Repolarization Evaluation With Human iPSC-CMs

Area of Science:

• Cardiovascular pharmacology
• Stem cell biology
• Drug safety assessment

Background:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for Comprehensive in vitro Proarrhythmia Assays (CiPA).
• Observed discrepancies in hiPSC-CM electrophysiological (EP) responses between serum and serum-free media (SFM) complicate cardiac safety evaluations for drug-induced QT prolongation and torsade de pointes (TdP).

Purpose of the Study:

• To compare hiPSC-CM EP responses to CiPA compounds in serum and SFM.
• To elucidate the cause of differing EP responses, specifically abiotic compound loss in SFM.
• To investigate how compound preparation impacts drug bioavailability and TdP risk prediction in different media.

Main Methods:

• Comparison of hiPSC-CM electrophysiological responses to 10 CiPA compounds and moxifloxacin in both serum-containing and serum-free media.
• Investigation of abiotic loss of hydrophobic compounds to plastic surfaces when prepared in SFM.
• Assessment of the impact of compound preparation methods on drug bioavailability in exposure media.

Main Results:

• Significant differences in hiPSC-CM electrophysiological responses were observed between serum and SFM.
• Abiotic loss of hydrophobic compounds to plasticware during preparation in SFM was identified as a key factor contributing to these differences.
• Compound preparation methods directly influence drug bioavailability and subsequent TdP risk prediction.

Conclusions:

• Abiotic loss of hydrophobic compounds in SFM is a critical consideration for accurate in vitro cardiac safety testing.
• Awareness of this phenomenon is essential for reliable QT prolongation and TdP risk assessment, particularly when extrapolating in vitro data to in vivo outcomes.
• Standardized compound preparation protocols are necessary for consistent and reproducible results in SFM-based assays.