Abstract
Introduction: Peramivir, anti-influenza drug, was reported to induce QT prolongation in some phase III studies. Such the effect on cardiac repolarization may have some potential to induce lethal ventricular arrhythmia, torsade de pointes (TdP). Accordingly, we characterized the cardiac safety pharmacological profile of peramivir by assessing ventricular and atrial electrophysiological actions in addition to cardiohemodynamic effects.
Methods: Peramivir in doses of 1 and 10 mg/kg/10 min (subtherapeutic and clinically-relevant doses, respectively) was intravenously administered to isoflurane-anesthetized dogs under the monitoring of electropharmacological variables (n=4).
Results: Peramivir decreased total peripheral vascular resistance, whereas it increased cardiac output and kept mean blood pressure at the basal control level. Meanwhile, peramivir prolonged QT interval/QTcV and Tpeak-Tend without altering J-Tpeakc or intra-atrial, atrioventricular as well as intra-ventricular conduction. Peramivir also delayed ventricular repolarization and increased refractoriness at the same site, and tended to prolong terminal repolarization period. Peramivir prolonged atrial effective refractory period, of which extent was smaller than those of existing anti-atrial fibrillatory drugs; moreover, its atrial selectivity was lower among the drugs.
Conclusion: The clinical dose exposure of peramivir can develop a substrate for inducing TdP, but may not provide its trigger, suggesting that it would have the least potential for the onset of TdP.
