QT PRODACT: usability of miniature pigs in safety pharmacology studies: assessment for drug-induced QT interval prolongation.
To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia's formula) by 8%-16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax=42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7%-12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Tokyo, Japan. m-kanou@oyc.co.jp
Mayumi
M
Kano
Tohru
T
Toyoshi
Sakae
S
Iwasaki
Masami
M
Kato
Masayoshi
M
Shimizu
Takao
T
Ota
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016208:Databases, Factual; D004562:Electrocardiography; D006220:Haloperidol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D023421:Models, Animal; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013015:Sotalol / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D013686:Telemetry
D011433:Propranolol; D013015:Sotalol; D006220:Haloperidol