QT prolongation and torsades de pointes induced by an antifungal agent, D0870, in conscious dogs
Introduction
D0870, which is chemically (R)-2-(2,4-difluoro-phenyl)-1-[3-[(E)-4-(2,2,3,3-tetrafluoropropoxy)-styryl]-1H-1,2,4-triazol-1-yl]-3-(1H-1,2,4-triazole-1-yl) propan-2-ol (Fig. 1), is a novel antifungal agent that is active orally and parenterally against a wide range of systemic mycosis, even in the immunocompromised models (Yamada et al., 1993). D0870 caused sudden deaths in the high-dose group (5 mg/kg/day) of a 6-month dog study (personal communication). Because the dogs were found dead or had died suddenly without any remarkable symptoms and showed no histopathologic changes in the heart, the cause of sudden death remains unknown. In contrast, we have already obtained apparent evidence for D0870-induced QT prolongation in dogs and monkeys. These findings suggest that the cause of the sudden death induced by D0870 may be drug-induced long QT interval syndromes (LQTS). The LQTS in humans presents characteristic electrocardiograms (ECGs) showing a prominent QT prolongation, ventricular premature contractions (VPCs), T-wave alternans, and repeated torsades de pointes (TdP) at the occurrence of seizures with syncope (Schwartz et al., 1995). Although QT prolongation and TdP are produced by many drugs (Jackman et al., 1988, Symanski and Gettes, 1993, Napolitano et al., 1994, Haverkamp et al., 1995, Schwartz et al., 1995) and many experimental models of TdP have been developed (Weissenburger et al., 1993), there are few reports on TdP induced by only one drug itself in conscious dogs. In the present study, we intended to elucidate the cause of the sudden death in dogs treated intravenously with D0870 in detail, based on the results of electrocardiographic analysis. To solve this issue quickly, it is essential to establish experimental conditions for a conscious dog model with a high incidence of sudden death induced by D0870. First, we evaluated the relation between QT prolongation and plasma concentration of D0870 in dogs by single intravenous dosing. Then, we conducted the study to induce, shortly and with high frequency, sudden deaths in dogs by using loading (50 mg/kg) and maintenance (5 mg/kg/day) doses with long-term ambulatory electrocardiographic monitoring in consideration of the long elimination half-life (ca. 3 days) of the drug in dogs (personal communication). We demonstrated that TdP preceding ventricular fibrillation (VF) is primarily responsible for the development of the sudden death induced by D0870, and have thus established a conscious dog model of TdP.
Section snippets
Test materials
An injectable preparation containing 50 mg of D0870 per 20 ml of a sterile lipid emulsion supplied from Zeneca Pharmaceuticals (Cheshire, UK) was used for this study. A 10% Intralipid™ emulsion purchased from Kabi Pharmacia (Dubendorf, Sweden) was used as the control vehicle. Since the chemical and biological stability of the preparation diluted with vehicle had not been validated, the preparation without dilution was used in this study. Therefore, the dosing volume was altered for each dose
Single dose study
Plasma concentrations of D0870 in the animals given 10 or 20 mg/kg decreased steeply for 2 or 3 h after dosing, maintained a plateau until 24 h, and then decreased slowly (Fig. 2). The plasma concentrations of D0870 in the animals given 1 or 2.5 mg/kg were 0.71 and 3.45 μg/ml, respectively, just after dosing, and were 0.37 and 0.79 μg/ml at 6 h.
No QTc prolongation was found in the animals given 1 or 2.5 mg/kg. The QTc intervals just after the dosing were prolonged by 23 and 28%, compared with
Discussion
To elucidate the cause of the sudden death in dogs treated intravenously with D0870, an antifungal agent, we first conducted a single dose study in dogs to evaluate the relation between plasma concentrations of D0870 and QT prolongation. We found a linear relation between QTc prolongation rate and plasma concentration of D0870, and estimated the threshold causing 10% QTc prolongation to be 3.8 μg/ml. This concentration is sufficiently higher than the 50% antibiotic concentration (0.0015 μg/ml)
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