Sensitive and reliable proarrhythmia in vivo animal models for predicting drug‐induced torsades de pointes in patients with remodelled hearts

Abstract

As an increasing number of non-cardiac drugs have been reported to cause QT interval prolongation and torsades de pointes (TdP), we extensively studied the utility of atrioventricular (AV) block animals as a model to predict their torsadogenic action in human. The present review highlights such in vivo proarrhythmia models. In the case of the canine model, test substances were administered p.o. at conscious state 44 weeks after the induction of AV block, with subsequent Holter ECG monitoring to evaluate drug effects. Control AV block dogs (no pharmacological treatment) survive for several years without TdP attack. For pharmacologically treated dogs, drugs were identified as high, low or no risk. High-risk drugs induced TdP at 1-3 times the therapeutic dose. Low-risk drugs did not induce TdP at this dose range, but induced it at higher doses. No-risk drugs never induced TdP at any dose tested. Electrophysiological, anatomical histological and biochemical adaptations against persistent bradycardia-induced chronic heart failure were observed in AV block dogs. Recently, we have developed another highly sensitive proarrhythmia model using a chronic AV block cynomolgus monkey, which possesses essentially the same pathophysiological adaptations and drug responses as those demonstrated in the canine model. As a common remodelling process leading to a diminished repolarization reserve may present in patients who experience drug-induced TdP and in the AV block animals, the in vivo proarrhythmia models described in this review may be useful for predicting the risk of pharmacologically induced TdP in humans.

Pharmacological characterization of <i>microminipig</i> as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies

“…Next, we examined the cardiovascular effects of dl-sotalol on the halothane-anesthetized microminipigs. We compared these results with those obtained by the halothane-anesthetized canine model (Ishizaka et al, 2008), since the canine model has been demonstrated to be useful for predicting the drug-induced cardiohemodynamic and electrophysiological responses in humans (Sugiyama, 2008). We found that each cardiovascular response was directionally the same as that reported in dogs, although the extent of the changes was greater in microminipigs than in dogs under the same anesthetic condition (Ishizaka et al, 2008).…”

“…Since net effect of β-adrenoceptor blocking activity of dlsotalol in microminipigs would be more potent than that in dogs as discussed above, dl-sotalol may more strongly suppress the constitutively operating inward Ca 2+ current in microminipigs than in dogs, which could counteract the consequence of I Kr and I Ks inhibition, resulting in the lack of change in the J-T peak c. These results may partly explain that torsade de pointes was not induced in the chronic atrioventricular block microminipigs following the administration of 10 mg/kg p.o. of dl-sotalol , although the lethal arrhythmia was observed with high reproducibility in the chronic atrioventricular block dogs (Sugiyama, 2008).…”

“…Induction of the halothane anesthesia prolonged the QT interval as well as QTcF in microminipigs, suggesting that the halothane anesthesia can reduce the cardiac repolarization reserve in microminipigs like in dogs (Sugiyama, 2008;Takahara et al, 2005). Next, we examined the cardiovascular effects of dl-sotalol on the halothane-anesthetized microminipigs.…”

“…Since the halothane-anesthetized dogs have been known to be effective and reliable for this purpose (Sugiyama, 2008), in this study we tried to establish the halothane-anesthetized microminipigs as an alternative model to the canine one. In order to characterize the halothane-anesthetized microminipigs, we firstly clarified the effects of halothane anesthesia by itself on the cardiovascular system of microminipigs.…”

“…dl-Sotalol is a potent I Kr -inhibitor with β-adrenoceptor blocking activity (Hohnloser and Woosley, 1994;Ishizaka et al, 2008), which has been used as a positive control for confirming the sensitivity and reliability of various animal models (Lynch et al, 2008;Sakaguchi et al, 2009;Sugiyama, 2008). In order to better analyze proarrhythmic potential of dl-sotalol with microminipigs, we adopted the corrected J-T peak interval (J-T peak c) and T peak -T end interval, which reflect the early and late repolarization phases, respectively.…”