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Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical  in vivo  experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl)  in vitro  and  in vivo . Co-applied with amiodarone, L-ala, S  P  prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala, R  P  produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed  in vivo . Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala, S  P  metabolites ± amiodarone, but no D-ala, R  P  metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala, S  P  prodrug metabolite formation, yet exacerbated L-ala, S  P  + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala, S  P  prodrug-dependent in cardiomyocytes.

Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry