JET, but not ‘snapshot’, analysis is sensitive enough to detect effects at critical concentrations of ondansetron and moxifloxacin in dog

Abstract

Jacketed external telemetry (JET) is an important technology allowing access to continuous ambulatory electrocardiogram data in settings in addition to standalone cardiovascular safety pharmacology studies such as GLP toxicology studies. In developing oncology therapeutics under ICH S9 it may also be the case that QTc data collected during toxicology studies is the only in vivo data available to support an integrated risk assessment under the new ICH E14 Q6.1. The current analyses compared JET in freely moving dogs with more conventional ‘snapshot’ collections in restrained, recumbent animals for the same group of 24 beagle dogs (12 M, 12F). The treatments tested were vehicle, ondansetron (3 and 10 mg/kg), and moxifloxacin (30 mg/kg). A parallel study design (3 animals per sex per group) was used in the comparison of JET and ‘snapshot’ collection. In a subsequent phase of the study the 12 male dogs were rotated through the other treatments to create a Latin square crossover analysis. The higher dose of ondansetron achieved Cmax exposures consistent with the clinical critical concentration associated with a 10 ms QTc prolongation. The tested dose of moxifloxacin was the same as that tested in previous studies and achieved a Cmax concentration ~ 3-fold the critical concentration associated with a 10 ms QTc prolongation and had sustained exposure throughout the 24 h telemetry collection period. No treatment related QTc effects were detected using ‘snapshot’ data collection. The small heart rate increase following moxifloxacin detected using JET was not detected in the ‘snapshot’ analysis. Statistically significant, treatment-related QTc prolongation was detected for both doses of ondansetron and moxifloxacin in the parallel and the cross-over JET data analyses. The study-specific least significant difference was 7.1 ms and 2.6 ms for these analyses, respectively. JET data collection and analysis in a parallel toxicology-like design proved sensitive enough to support ICH E14 Q6.1 integrated risk assessment. Conventional ‘snapshot’ analysis was not sufficiently sensitive to detect a treatment-related effect even for modest multiples of the human critical concentrations.