Evaluation of the guinea pig monophasic action potential (MAP) assay in predicting drug-induced delay of ventricular repolarisation using 12 clinically documented drugs.
BACKGROUND
While the dog in vivo model is commonly employed in the later phase of discovery for assessing drug-induced QT prolongation, an early screening assay is valuable when selecting compounds for further development and when compound availability usually is low. One such screening assay is the anaesthetised guinea pig monophasic action potential (MAP) model. The aim of the present study was to evaluate the ability of this model to detect proarrhythmic properties by testing a set of reference compounds with known clinical profile. Moreover, these results were compared to data previously obtained using in vivo canine QT assays (QT PRODACT study).


METHODS
Anaesthetised and ventilated male guinea pigs were vagotomised and pretreated with propranolol. After thoracotomy, a pacing electrode was clipped to the left atrial appendage and a suction MAP electrode positioned on the left ventricular epicardium. The drug or corresponding vehicle was injected intravenously in cumulative doses and MAP duration at 90% repolarisation (MAPD90) was recorded during cardiac pacing.


RESULTS
The 8 drugs known to be proarrhythmic in the clinic all displayed dose-dependent prolongation of MAPD90, while the 4 drugs devoid of dysrhythmia in man had no effect. When comparing doses producing a 10% MAPD90 increase with doses reported to increase QTc by 10% in dogs a strong correlation was seen (R(2) 0.94 and 0.58 for anaesthetised and conscious dogs, respectively).


CONCLUSIONS
The guinea pig MAP assay identified all clinically positive drugs while negative drugs were without effect on ventricular repolarisation. Furthermore, a good concurrence is shown between the guinea pig and dog models in identifying compounds with proarrhythmic properties. Overall, the study reinforces the anaesthetised guinea pig MAP model as a reliable assay predicting QT liability of new chemical entities and as a highly sensitive early screening model for cardiovascular risk.
Kågström
Jens
J
Safety Pharmacology, Safety Assessment Sweden, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden. jens.kagstrom@astrazeneca.com
Sjögren
Eva-Lena
EL
Ericson
Ann-Christin
AC
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000658:Amoxicillin / Q000008:administration & dosage; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D015764:Bepridil / Q000008:administration & dosage; D002216:Captopril / Q000494:pharmacology; D020117:Cisapride / Q000008:administration & dosage; D004155:Diphenhydramine / Q000008:administration & dosage; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D006168:Guinea Pigs; D006220:Haloperidol / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010868:Pimozide / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D011433:Propranolol / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D016593:Terfenadine / Q000008:administration & dosage; D013881:Thioridazine / Q000008:administration & dosage; D014628:Vagotomy; D016276:Ventricular Function / Q000187:drug effects
D004364:Pharmaceutical Preparations; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D010868:Pimozide; D015764:Bepridil; D016593:Terfenadine; D000658:Amoxicillin; D004155:Diphenhydramine; D002216:Captopril; D011433:Propranolol; D006220:Haloperidol; D013881:Thioridazine; D001241:Aspirin; D020117:Cisapride