Simple-to-use, reference criteria for revealing drug-induced QT interval prolongation in conscious dogs

Electrocardiogram (ECG) QT interval prolongation produced by drugs in certain animal models is currently believed to be predictive of cardiac proarrhythmic effects in humans. For this reason, nonclinical assessment of the effects of novel drugs on cardiac repolarization is a regulatory prerequisite for progressing such agents to clinical evaluation. The present investigation was carried out to develop reliable, simple-to-use reference criteria for identifying individual animals as responders to drugs that prolong the QT interval. ECG were recorded for 30 s at 0 (8 am), 2, 4, 6 and 24 h in 6 trained, conscious, beagle dogs during 5 control experimental sessions. QT intervals were measured and corrected for heart rate by applying the Van de Water algorithm (QTc). The maximal (QTcmax) and minimal (QTcmin) values of QTc observed in each of the five control recording sessions were noted. Two reference (R) criteria were used to designate an individual animal as a responder to drug treatment: 1) QTcmaxR which was obtained by adding 10 ms to the largest value of QTcmax observed during the five control recording sessions and 2) (QTcmax−QTcmin)maxR which was obtained by increasing by 50% the largest of the (QTcmax−QTcmin) values [(QTcmax−QTcmin)max] observed in the 5 control recording sessions. The sensitivity and reliability of these criteria were tested by determining QTc intervals before and 2, 4, 6 and 24 h after placebo or quinidine (200, 400 and 800 mg p.o. per animal). The reference values of QTcmaxR and (QTcmax−QTcmin)maxR for the various dogs ranged from 246 to 270 ms and from 15 to 19.5 ms, respectively. The number of dogs responding to treatment (T: quinidine at 200, 400 and 800 mg, p.o. per animal) with a QTcmaxT and/or a (QTcmax−QTcmin)maxT equal to or greater than the respective reference values was, respectively, 1/6, 3/6 and 5/6 dogs. Additionally, the number of responders correlated well with the concentration of free quinidine in the plasma. In conclusion, this investigation succeeded in establishing reliable, reference criteria for individual dogs despite the intrinsic daily variation of QTc interval. The application of these criteria allowed identifying individual animals responding to quinidine with delayed cardiac repolarization.