Translation of hemodynamic effects between anesthetized guinea pig and conscious rat models

Abstract

The aims of these studies were to evaluate correlations between ECG changes in the anesthetized cardiovascular guinea pigmodel (CVGP), to ion channel inhibition and to ECG changes in non-rodent telemetry models and human. Results: We compared the effects of 38 compounds on ion channel inhibition to their ECG effects in the CVGP. The CVGP proved to be highly sensitive for detecting QTc, PR and QRS interval prolongation mediated by hERG, hCav1.2 and hNav1.5 inhibition, respectively. Strong correlations between ion channel inhibitory potencies and the free plasma concentrations producing 10% prolongation of the QTc, PR or QRS interval in the CVGP were noted. In addition, changes in the QTc, PR and QRS intervals were 92%, 92% and 100% predictive of the effects observed in non-rodent telemetry models. The CVGP proved to be 100% specific and 88%, 75% and 100% sensitive for QTc, PR and QRS prolongation, respectively. Similarly, the free plasma concentrations that prolong theQTc, PR andQRS in CVGP translated verywell to clinical data. Conclusions: The CVGP is a sensitive model for assessing QTc, PR and QRS prolongation elicited by effects on hERG, Cav1.2 and Nav1.5, respectively. The CVGP model is also predictive of ECG changes observed in non-rodent telemetry and humans. As such, it should be considered a valuable tool as part of an integrated risk assessment.