The statistical and pharmacological sensitivity of nonclinical QTc analysis comparing jacketed telemetry and...

Quantitative QTc assessment in toxicology studies can use one of two techniques, either continuous telemetry recording in ambulatory animals or short snapshots of electrocardiograms recorded using multilead electrodes in restrained animals. QTc assessments can augment clinical QTc data in regulatory submissions provided both the statistical and pharmacological sensitivity can be demonstrated. Analyses in dogs (N = 24) used both jacketed external telemetry (ET) and short segment or 'snapshot' (SS) multilead recordings in separate phases. Three groups (moxifloxacin, and two doses of ondansetron) were compared to a vehicle group. In phases 1 and 2, one group received moxifloxacin (30 mg/kg), two received doses of ondansetron (3 and 10 mg/kg), and the last received vehicle (0.5 % (w/v) methylcellulose in deionized water) in a parallel group study design. The third phase of the study involved the original 12 male dogs receiving all treatments in a randomized triple Latin square design. ET (n = 6/group) detected a significant effect on QTc of moxifloxacin for all but one hour of the postdose period and detected an effect at fewer timepoints with ondansetron in a dose- and exposure-dependent manner. QTc prolongation at a single timepoint was significant for both the lower dose of ondansetron and moxifloxacin using SS. SS did not detect any significant QTc effect at the higher dose of ondansetron. In the cross-over phase (ET only), moxifloxacin significantly prolonged the QTc interval through all but one hour of the post dose period. Low dose ondansetron did not significantly prolong the QTc interval while there was a small dose-dependent effect with isolated time points being significant with the higher dose. The least significant differences detectable were approximately 9 (ET), 17 (SS) and 5 ms (ET with Latin square) for the three phases, respectively. These analyses demonstrate the statistical and pharmacological sensitivity of the techniques commonly used in large animal toxicology studies. Overall, QTc assessment using telemetry is the more sensitive and consistent technique and is a model sufficiently sensitive to supplement clinical QTc assessment.