Abstract

Identification of the Cellular Effects of Sofosbuvir and Amiodarone using hiPSC-Derived Cardiomyocytes

Sonja Stoelzle-Feix, Director Scientific Affairs, Nanion

Sofosbuvir-based drugs have significantly advanced care for hepatitis C virus (HCV)-infected patients. While exhibiting a clean safety profile throughout development, recent post-marketing reports indicate that severe symptomatic bradycardia can occur through combined administration of sofosbuvir and amiodarone. The underlying cellular mechanism of this drug-drug interaction remains unknown. Here, we present a mechanistic interrogation of the cellular effects of sofosbuvir and amiodarone using human stem cell derived cardiomyocytes (hSC-CMs), multiwell microelectrode array (MEA), automated patch clamp (APC), and impedance measurements. MEA recordings demonstrated that sofosbuvir alone had no effect on hSC-CM electrophysiology, but reversed the effects of amiodarone when added in combination, leading to a 53 % decrease in field potential duration and 100 % increase in spontaneous beat rate relative to vehicle controls. APC assays demonstrated that the drug combination did not block potassium, sodium, or calcium currents beyond the assay controls. Simultaneous MEA and impedance measurements revealed differential responses on electrical and contractile activity; hSC­CMs remained electrically active while contractile activity ceased within ~2 hours of application with the drug combination. The impact on cardiomyocyte electrophysiology and contractility without a direct effect on ion channel activity suggests that the combination of amiodarone and sofosbuvir may impair intracellular calcium handling. These results demonstrate the importance of measuring multiple endpoints within the functional excitation-contraction cascade and, more generally, reinforce the utility of hSC-CMs as an integrated assessment of cardiac safety liability in vitro.