Host: The Japanese Society of Toxicology
The preclinical studies for clarifying a cardiovascular risk of new chemical entity are critical in drug development because cardiovascular effects could be associated with a life-threatening adverse event. To evaluate a cardiovascular risk before FIH, in vivo telemetry study using conscious and non-restricted animals is generally conducted as the safety pharmacology study. Several cardiovascular parameters (e.g. blood pressure, heart rate, ECG) are assessed in the study, and QT prolongation in ECG is regarded as the primary surrogate biomarker to investigate the potential for life-threatening arrhythmia (Torsade de pointes). Concerning the progress of preclinical QT evaluation, a most effective probabilistic rate-correction method (Holzgrefe et al., 2007) was widely adopted during the past decade. Additionally, a translational discussion of drug-induced QT effects from animals to humans is accelerated based on the clinical IQ-CSRC study to characterize the effects of QT reference drugs on the concentration-QT relationship by exposure-response (ER) analysis (Darpo et al., 2014). We would like to introduce a J-ICET (Japan activity for Improvement of Cardiovascular Evaluation by Telemetry system) consortium activity and its results of preclinical QT evaluation by ER analysis in cynomolgus monkeys using QT reference drugs in crinical study (Darpo et al., 2015), and have a discussion about the latest topics (e.g. T wave analysis, automated blood sampling device) and future perspectives of preclinical in vivo studies for evaluating proarrhythmic potential.
