Differential QTc prolonging effects of dofetilide and HMR1556 in rabbits and guinea pigs

Abstract

The sensitivity to QT-prolonging drugs varies between species due to differences cardiac electrophysiology and ion channel expression. Rabbits are often used in cardiac safety pharmacology because their depolarization and repolarization characteristics are similar to humans. Rabbits tend to be sensitive to QT-prolonging drugs due to their reliance on IKr for repolarization. Guinea-pigs have a different cardiac electrophysiological profile; They exhibit a greater reliance on IKs rather than IKr. ECG telemetry probes were implanted in 8 adult male guinea pigs and 8 rabbits followed by 5 days of recovery. The IKr blocker dofetilide (10 μg/kg i.v.) and the IKs blocker HMR1556 (400 ng/kg i.v.) were administered by 10-min infusion alone or in combination. Dofetilide alone caused a 77 ms (rabbit) and 27 ms (guinea pig) peak QTc (Bazett's) prolongation. HMR1556 alone caused a 15 ms (rabbit) and 11 ms (guinea pig) peak QTc prolongation. Torsades de pointes (TdP) were recorded in 3/8 rabbits (dofetilide) and 4/8 guinea pig (HMR1556), and lasted 21 s on average. Administered together, dofetilide and HMR1556 caused 81 ms (rabbit) and 41 ms (guinea pig) peak QTc prolongations. TdP were observed in 5/8 rabbits and 6/8 guinea pigs after 10-min infusions of the combined blockers. In all cases, the TdP self-arrested within 170 s. None of the animals died. These results illustrate the additivity of ion channel inhibition across two species, which suggests that the more QT-sensitive rabbit is particularly useful to assess the impact of known IKr blockers while guinea pigs offer a broader screening potential, especially for drugs that might affect multiple ion channels. Results from rabbit studies should be more predictive of human responses to IKr blockers.