Different species require different correction factors for the QT interval.

The ICH S7B guideline specifically requests the evaluation of the QT interval in in vivo models as an accepted risk factor for fatal tachyarrythmias. While it recommends correcting the QT interval for heart rate (HR), it also concedes that such corrections can yield misleading results. Data acquired from 40 cynomolgus monkeys (CM) and 66 Beagle dogs (BD) on 64 and 166 episodes, respectively, of 25-h ECG data collection in healthy control group animals were analyzed for this publication. The total number of ECGs evaluated was 10,761 (CM) and 24,882 (BD). The two species appear to have some difference in cardiac repolarization regulatory mechanisms. CM are more subject to diurnal fluctuations of autonomic nervous tone, which leads to dramatic variation of QT interval duration (up to 12.7%) at the same HR (60 to 70 bpm) in different light cycles. BD do not have such a variation. Different species require different QT correction formulas. Van de Water's correction provides optimal results in BD; Bazett's correction presents optimal results in CM. Fundamental behavioral differences (domesticated vs wild animals) may require individual approaches in the interpretation of the safety pharmacology studies in various species.

Variations in hemodynamic parameters and ECG in healthy, conscious, freely moving telemetrized beagle dogs.

Interpretation of the dynamic cardiovascular parameters on safety pharmacology studies is a challenging process; sometimes, it is difficult to separate normal physiological variations from the effects of the test drug. Data from healthy control Beagle dogs (41 males and 25 females) implanted with telemetry transmitters (DSI, St. Paul, MN) from 34 studies performed from 2003 to 2005 were analyzed. Telemetry data were collected for a 30-s period every 10 min for 24 h after sham dosing. One-hour averages were analyzed. Prior to dosing, heart rate (HR) was 95.6 +/- 26.6 bpm; mean, systolic, and diastolic blood pressure (BP) were 105.3 +/- 12.7, 142.5 +/- 5.3, and 84.7 +/- 11.1 mmHg, respectively. PR, QRS, QT, and corrected (Van de Water) QT intervals were 121 +/- 13, 33 +/- 3, 217 +/- 23, and 245 +/- 18 ms, respectively. Seasonal and slight diurnal patterns were noticed only in HR; BP and body temperature were more stable. PR and QT intervals were inversely related to HR; in addition, the duration of PR was influenced by the light cycle. A comparison of three QT correction formulas demonstrated that Van de Water's formula provided the optimal results in Beagle dogs over a wide range of HR.