ECG telemetry in conscious guinea pigs.

INTRODUCTION: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required. METHODS: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs. RESULTS AND CONCLUSION: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to ß-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment.

Safety pharmacology assessment of drug-induced QT-prolongation in dogs with reduced repolarization reserve.

INTRODUCTION: Drug-induced QT-prolongation, often based on hERG K+ current inhibition, has become a major safety concern during drug development. Hence, regulatory guidelines require combined in vitro and in vivo assays to assess the potential of new chemical entities to delay ventricular repolarization. Here, results of a pharmacological validation study with the torsadogenic compound sotalol are presented. METHODS: Alteration of ECG parameters was investigated in both conscious and anesthetized Beagle dogs (cumulative infusions of D,L-sotalol; n=6). The repolarization reserve of the latter was reduced by neurolept anesthesia using the hERG blocker droperidol (0.25 mg/kg/h yielding mean plasma concentrations of 0.5 microM). Furthermore, hERG K+ current and action potentials (AP; rabbit Purkinje fibers) were measured in vitro. RESULTS: The Fridericia corrected QT interval, QTcF, in conscious dogs (control: 254+/-15 ms), was dose-dependently prolonged by D,L-sotalol (+42 ms at plasma levels of 261 microM; dose 30 mg/kg). In anesthetized dogs, baseline QTcF (337+/-35 ms) was already prolonged compared to conscious dogs. In addition, QTcF-increase (+90 ms) was more pronounced at lower D,L-sotalol plasma levels (181 microM; dose 10 mg/kg), and proarrhythmic markers Tpeak-Tend and short term variability of QT were increased. These in vivo findings are supported by in vitro data. The hERG K+ current was blocked by D,L-sotalol (IC50 approximately 1.2 mM, IC20 approximately 250 microM) and droperidol (IC50 approximately 0.1 microM, IC20 approximately 0.02 microM). Purkinje fiber APs were concentration-dependently prolonged by D,L-sotalol (APD90:+60% at 30 microM) and droperidol (APD90:+55% at 1 microM). Low droperidol concentrations increased the sensitivity of Purkinje fibers towards D,L-sotalol-mediated AP prolongation. DISCUSSION: In conclusion, the higher sensitivity of anesthetized dogs towards sotalol-induced QT-prolongation is due to a reduced cardiac repolarization reserve caused by the hERG blocker droperidol. Hence, the droperidol-/fentanyl-/N2O-anesthetized dog is a particularly sensitive animal model for the detection of drug-induced QT-prolongation in safety pharmacology studies.