The cardiovascular and pharmacokinetic profile of dofetilide in conscious telemetered beagle dogs and cynomolgus monkeys

Abstract

Background and purpose: The effects of dofetilide were studied in monkeys and dogs. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure.

Experimental approach: Beagle dogs and cynomolgus monkeys were telemetered to collect arterial blood pressure, heart rate and ECG for 6 h after selected oral doses of dofetilide. Pharmacokinetic parameters were determined for each dose.

Key results: Dogs: increases in the QT(c) interval reached 56 ms in dogs dosed with 0.3 mg kg(-1) of dofetilide. Premature ventricular contractions and right bundle branch block were evident at this dose, without changes in cardiovascular parameters. The mean C(max) values were 3.35 and 60.15 ng mL(-1) at doses of 0.03 and 0.3 mg kg(-1), respectively. Monkeys: increases in QT(c) intervals reached 40-50 ms after 0.03 mg kg(-1). T-wave changes were observed after 0.03 mg kg(-1) without changes in cardiovascular parameters. The mean C(max) values following oral doses of 0.01 and 0.03 mg kg(-1) were 0.919 ng mL(-1) and 1.85 ng mL(-1), respectively.

Conclusions and implications: Despite dofetilide exposure comparable to that in humans, QT(c) responses in dogs were greater than those reported in humans. A comparable human dose used in the monkey achieved only half of the exposure but was associated with twofold greater increases in QT(c). Our data support the view that safety risk assessments of new drugs in animal models should ensure that the clinical therapeutic range of exposure is achieved and any untoward effects interpreted accordingly.

Figure 1

Baseline adjusted QT_c interval averages in beagle dogs. Comparison of baseline adjusted QT_c intervals (±s.e.mean) for dogs given 0.03 or 0.3 mg kg⁻¹ dofetilide. Inset: dofetilide plasma levels from subset of dogs encompassing the cardiovascular monitoring period.

Figure 2

Baseline adjusted QT_c interval averages in cynomolgus monkeys. Comparison of baseline adjusted QT_c intervals (±s.e.mean) for cynomolgus monkeys given 0.01 or 0.03 mg kg⁻¹ dofetilide. Inset: dofetilide plasma levels from subset of monkeys encompassing the cardiovascular monitoring period.

Figure 3

(a, b) Dofetilide concentrations (ng mL⁻¹) with superimposed examples of QT interval prolongation recorded during the cardiovascular phase of the investigation in dog, 0.3 mg kg⁻¹ (a) and monkey, 0.03 mg kg⁻¹ (b).

Figure 4

Example of dofetilide-induced torsades de pointes in the cynomolgus monkey after a dose of 0.2 mg kg⁻¹. The upper trace depicts arterial blood pressure and the lower trace shows Lead II ECG and an example of a short episode of self-terminating torsades de pointes (bar below ECG trace), which returned to sinus rhythm shortly thereafter. Note the ECG irregularities preceding the torsades de pointes.