Nonclinical cardiovascular safety assessment of thioridazine: Impact of autonomic tone, body temperature, and choice of species.

Pending updates to ICH S7B/E14 guidelines will enable the substitution of human TQT studies with support from concomitant negative hERG and non-rodent CV studies. This retrospective analysis compared the effects of thioridazine (THD) (5-20 mg/kg) on heart rate (HR), blood pressure (BP), body temperature (Tc), and QT in the dog (n = 6), cynomolgus monkey (n = 4), and Goettingen minipig (n = 4) with data from previously completed studies employing crossover designs. As QT measurements are confounded by HR and Tc changes, QT effects were individually corrected for changes in HR (QTca) and Tc (QTcaT). THD-induced hemodynamic changes seen in humans were most accurately reflected in the monkey and, to a lesser extent, the dog, but not in the minipig. The minipig was most sensitive to THD QTc effects. When QTca was adjusted for THD-associated Tc decreases in minipigs and monkeys, the minipig revealed a lessened but pronounced QTcaT increase (48 ms). In the monkey, a persistent QTca increase was reduced to only a transient (0.5-3 h) QTcaT increase (20 ms). The dog's lack of THD QTca effects triggered co-administration of atenolol (AT) to attenuate THD-induced HR increases in the dog and monkey. THD + AT revealed peak QTcaT increases of 32 ms in the dog and 40 ms in the monkey, suggesting potential autonomic nervous system (ANS) interference in detecting repolarization changes. These results highlight critical species-specific differences in the outcome of parallel safety investigations. Species selection for nonclinical safety studies should consider the potential impact of Tc and ANS effects to avoid false-negative or overly positive outcomes.

Comparison of telemetry and high-definition oscillometry for blood pressure measurements in conscious dogs: effects of torcetrapib.

This study compared torcetrapib-induced blood pressure (BP) changes simultaneously obtained by high-definition oscillometry (HDO) and telemetry. Male beagles (n = 6) received single oral doses of vehicle or torcetrapib at 10 or 30 mg/kg; BP were acquired simultaneously by HDO and telemetry from 2 h before dosage until 7 h afterward. Systolic, diastolic, and mean arterial pressures (MAP) and heart rate were compared by using Altman-Bland agreement analysis. Dogs were allocated into subgroups according to temperament and baseline MAP (less than 110 mm Hg and 110 mm Hg or greater). Both methods demonstrated high precision. HDO recordings exhibited higher variability for all parameters (inclusive MAP SDs were 7.0 +/- 2.7 mm Hg for HDO compared with 3.4 +/- 1.9 mm Hg for telemetry), accompanied by a positive bias for all pressures (systolic, 10.4 mm Hg; diastolic, 5.7 mm Hg; MAP, 1.9 mm Hg). Both methods detected similar maximal increases in MAP with 30 mg/kg torcetrapib (HDO, 15.8 +/- 10.4 mm Hg; telemetry, 15.8 +/- 5.3 mm Hg). No significant effects were noted for heart rate. Torcetrapib elicited a dose-dependent increase in BP in dogs with baseline MAP of less than 110 mm Hg, whereas increases were maximal with 10 mg/kg in the other group, and dose-dependence was no longer observed. BP changes were influenced by animal temperament, demonstrating that HDO results must be interpreted with caution. HDO may provide a useful and accurate method for noninvasive BP measurements in canine studies.