title: The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. pierremorissette@hotmail.com
authors: Pierre
authors: P
authors: Morissette
authors: Masahiro
authors: M
authors: Nishida
authors: Elena
authors: E
authors: Trepakova
authors: John
authors: J
authors: Imredy
authors: Armando
authors: A
authors: Lagrutta
authors: Alysia
authors: A
authors: Chaves
authors: Kimberly
authors: K
authors: Hoagland
authors: Chao-Min Lei
authors: CM
authors: Hoe
authors: Matthew M
authors: MM
authors: Zrada
authors: Jeffrey J
authors: JJ
authors: Travis
authors: Gloria J
authors: GJ
authors: Zingaro
authors: Pamela
authors: P
authors: Gerenser
authors: Greg
authors: G
authors: Friedrichs
authors: Joseph J
authors: JJ
authors: Salata
mesh_terms: D000758:Anesthesia; D000818:Animals; D015195:Drug Design; D004562:Electrocardiography; D006168:Guinea Pigs; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D023421:Models, Animal; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013686:Telemetry; D018675:Toxicity Tests / Q000379:methods
chemical_list: D007473:Ion Channels
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