The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model

Abstract

Introduction: In recent years, the anesthetized guinea pig has been used increasingly to evaluate the cardiovascular effects of drug-candidate molecules during lead optimization prior to conducting longer, more resource intensive safety pharmacology and toxicology studies. The aim of these studies was to evaluate the correlations between pharmacologically-induced ECG changes in the anesthetized cardiovascular guinea pig (CVGP) with ECG changes in conscious non-rodent telemetry models, human clinical studies and effects on key cardiac ion channels.

Methods: We compared the effects of 38 agents on ion channel inhibition to their ECG effects in the CVGP. 26 of these agents were also evaluated in non-rodent telemetry and compared to the results in the CVGP.

Results: The CVGP was highly sensitive for detecting QTc, PR and QRS interval prolongation mediated by inhibition of hERG, hCav1.2 and hNav1.5, respectively. There were robust correlations between ion channel inhibitory potencies and the free plasma concentrations (Cu) producing prolongation of the QTc, PR or QRS interval. Further evaluation showed that ECG changes in the CVGP were predictive of their effects on the QTc, PR and QRS intervals in non-rodent telemetry models with 92%, 92% and 100% accuracy, respectively. The CVGP proved to be 100% specific and 88%, 75% and 100% sensitive for QTc, PR and QRS interval prolongation, respectively. Similarly, the Cu that prolonged the QTc, PR and QRS in CVGP and humans correlated well.

Discussion: The CVGP is a sensitive model for assessing QTc, PR and QRS prolongation elicited by effects on hERG, hCav1.2 and hNav1.5, respectively. ECG changes in the CVGP are predictive of changes in non-rodent telemetry models and in humans (QTc). ECG parameters can be reliably evaluated with the CVGP model which increases the efficiency of CV derisking. Importantly, the design and implementation of this model is consistent with the "3Rs" for animal research.

Keywords: 3Rs; Anesthetized guinea pig; Assay sensitivity and specificity; CVGP; Cu; ECG; GP; ICH S7A and S7B; IKr; IKs; In vivo assay performance; NCE; Non-rodent telemetry; PPB; QTc; Safety pharmacology; TdP; Translation; anesthetized cardiovascular guinea pig; free plasma concentration; guinea pig; hCav1.2; hERG; hNav1.5; human L-type calcium current; human cardiac Na+ channel α-subunit; human ether-a-go-go related gene; new chemical entity; plasma protein binding; rapidly activating delayed rectifier potassium current; slowly activating delayed rectifier potassium current; the heart rate corrected QT interval; torsades de pointes.