EFFECT OF AMIODARONE AND HCV DAAS ON CARDIAC CONDUCTION IN NONCLINICAL STUDIES

【Objectives】Serious cases of symptomatic bradycardia have been reported in patients taking amiodarone with Sofosbuvir in combination with an HCV DAA. The effect of amiodarone and DAAs, alone and in combination, on cardiac conduction in guinea pig isolated hearts, and in vitro inhibition of human calcium channels were determined.
【Methods】The effect of amiodarone, daclatasvir, simeprevir, sofosbuvir and GS-331007 alone or in combination at their maximal concentrations achieved in plasma, on cardiac conduction was determined. Manual whole cell patch clamp electrophysiology were used on CHO or HEK cells stably expressing human calcium channels Cav1.2 or Cav3.2, respectively, to evaluate the onset and steady inhibition of peak current. The percent inhibition for block of Cav1.2 and Cav3.2 was determined.
【Results】Amiodarone, in the presence of the DAAs caused additive to synergistic prolongation of the atrial-to-His bundle interval. In vitro studies assessing inhibition of calcium channels in vitro are being conducted to understand the mechanism for the observation in guinea pig hearts with amiodarone and DAA and the findings will be presented.
【Conclusions】The symptomatic bradycardia observed with coadministration of amiodarone and sofosbuvir in combination with another DAA may be due to a pharmacodynamic interaction resulting in potentiation of the effect of amiodarone.