Long-term stability, reproducibility, and statistical sensitivity of a telemetry-instrumented dog model: A 27-month longitudinal assessment

Abstract

Introduction: ICH guidelines, as well as best-practice and ethical considerations, provide strong rationale for use of telemetry-instrumented dog colonies for cardiovascular safety assessment. However, few studies have investigated the long-term stability of cardiovascular function at baseline, reproducibility in response to pharmacologic challenge, and maintenance of statistical sensitivity to define the usable life of the colony. These questions were addressed in 3 identical studies spanning 27months and were performed in the same colony of dogs.

Methods: Telemetry-instrumented dogs (n=4) received a single dose of dl-sotalol (10mg/kg, p.o.), a β1 adrenergic and IKr blocker, or vehicle, in 3 separate studies spanning 27months. Systemic hemodynamics, cardiovascular function, and ECG parameters were monitored for 18h post-dose; plasma drug concentrations (Cp) were measured at 1, 3, 5, and 24h post-dose.

Results: Baseline hemodynamic/ECG values were consistent across the 27-month study with the exception of modest age-dependent decreases in heart rate and the corresponding QT-interval. dl-Sotalol elicited highly reproducible effects in each study. Reductions in heart rate after dl-sotalol treatment ranged between -22 and -32 beats/min, and slight differences in magnitude could be ascribed to variability in dl-sotalol Cp (range=3230-5087ng/mL); dl-sotalol also reduced LV-dP/dtmax 13-22%. dl-Sotalol increased the slope of the PR-RR relationship suggesting inhibition of AV-conduction. Increases in the heart-rate corrected QT-interval were not significantly different across the 3 studies and results of a power analysis demonstrated that the detection limit for QTc values was not diminished throughout the 27month period and across a range of power assumptions despite modest, age-dependent changes in heart rate.

Discussion: These results demonstrate the long-term stability of a telemetry dog colony as evidenced by a stability of baseline values, consistently reproducible response to pharmacologic challenge and no diminished statistical sensitivity over time.

Keywords: Dog; Drug discovery; Heart rate; Hemodynamics; In vivo; QT-interval; Safety pharmacology; Telemetry; dP/dt; dl-sotalol.