Monophasic action potential in anaesthetized guinea pigs as a biomarker for prediction of liability for drug-induced delayed ventricular repolarization.
BACKGROUND
Drug-induced QT interval prolongation has been one of the critical issues for developing new chemical entities and pharmaceutical companies need to evaluate the risk early in the development stage. At such stage, guinea pigs are appropriate due to their small size requiring only small amounts of test drugs. The purpose of this study was to determine the utility of guinea pig monophasic action potential (MAP) using 12 reference drugs in order to clarify prediction of the QT interval prolonging risk.


METHODS
Male guinea pigs were anaesthetized with pentobarbital (40 mg/kg, i.p.). Parameters analyzed were epicardial MAP duration (MAP(90)) at sinus rhythm (MAP(90(sinus))) and MAP(90) during atrial pacing (MAP(90(pacing))). Test drugs were administered to animals intravenously and cumulatively.


RESULTS
Vehicle control did not affect the parameters tested. All 8 QT-prolonging drugs prolonged MAP(90(sinus)) and MAP(90(pacing)) dose-dependently, whereas all 4 non-QT-prolonging drugs showed no or very slight prolongations of these MAP(90) parameters. Rank order potency of MAP(90(pacing)) prolongations by the QT-prolonging drugs tended to correspond to clinical plasma concentrations associated with QT interval prolongations or Torsades de Pointes but showed less of a link with hERG inhibition activities.


CONCLUSIONS
The present study demonstrates that the MAP model using anaesthetized guinea pigs could predict the liability of drugs for QT interval prolongation with high accuracy. QT assessment using the combination of the hERG assay with high sensitivity and the current in vivo assay would be desirable for early risk assessment within drug development.
Tabo
Mitsuyasu
M
Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan. tabomty@chugai-pharm.co.jp
Kimura
Kazuya
K
Ito
Shigeo
S
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D015415:Biomarkers; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D006168:Guinea Pigs; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000097:blood; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016171:Torsades de Pointes / Q000139:chemically induced*; D016276:Ventricular Function / Q000187:drug effects
D015415:Biomarkers; D004364:Pharmaceutical Preparations