Sensitivity and Reliability of Halothane‐anaesthetized Microminipigs to Assess Risk of Drug‐induced Long QT Syndrome

Abstract

Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 μg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane-anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.

Electropharmacological characterization of <i>microminipigs</i> as a laboratory animal using anti-influenza virus drug oseltamivir

“…Namely, we assessed the effects of pilsicainide, verapamil and E-4031 on microminipigs, which preferentially suppress Na + , Ca 2+ and K + channels, respectively (Matsukura et al, 2017); those of dl-sotalol, which can block both ß adrenoceptor and K + channel (Yokoyama et al, 2017); and those of moxifloxacin and terfenadine, which inhibit various cardiac ionic channels, leading to benign and malignant QT-interval prolongation, respectively . We have also compared those with the beagle dogs in our previous studies using the same experimental conditions, and shown that microminipigs may have smaller effective volume of drug distribution; greater basal sympathetic tone resulting in lessened hypotension-induced, reflex-mediated increase of sympathetic tone; and/or smaller repolarization reserve than beagle dogs (Cao et al, 2017;Matsukura et al, 2017;Yokoyama et al, 2017).…”

“…Microminipigs are extraordinarily small-sized miniature pigs, weighing approximately 7 kg at 6 months of age when they mature, which were developed by Fuji Micra Inc. (Shizuoka, Japan) (Kaneko et al, 2011). We have pharmacologically characterized microminipig as an in vivo laboratory animal for safety pharmacology study under halothane-anesthesia using several typical cardiac ion channel and receptor modulators (Cao et al, 2017;Matsukura et al, 2017;Yokoyama et al, 2017). Namely, we assessed the effects of pilsicainide, verapamil and E-4031 on microminipigs, which preferentially suppress Na + , Ca 2+ and K + channels, respectively (Matsukura et al, 2017); those of dl-sotalol, which can block both ß adrenoceptor and K + channel (Yokoyama et al, 2017); and those of moxifloxacin and terfenadine, which inhibit various cardiac ionic channels, leading to benign and malignant QT-interval prolongation, respectively .…”

<i>In vivo</i> characterization of rate-dependent impact on the QT interval of <i>microminipig</i> assessed by atrial electrical pacing: Development of correction formulae of QT interval

“…Microminipig is an extraordinarily small-sized miniature pig, which has been characterized as an alternative in vivo experimental model animal to dogs and monkeys for life science research including pharmacological and toxicological studies [1, 3, 5, 7-11, 16, 18]. Although electropharmacological studies have been extensively performed using the halothane-anesthetized microminipig [1, 3,5,9,10,16,18], it is still unknown how much the conventional correction formulae described above can attenuate the heart rate-dependent impacts on the QT interval of microminipig and how much difference is present in the amount of ventricular IKs current among microminipigs, humans and dogs. In order to answer such questions, we tried to develop correction formulae for microminipigs by adopting atrial electrical pacing protocol, which were compared with the conventional ones for humans and dogs [13].…”

“…The current correction formulae were developed by using the data obtained from 5 male microminipigs, the number of which might be too small to apply these formulae to the global population of microminipigs. Accordingly, we assessed whether the new correction formulae could properly correct the QT interval by using previously obtained experimental results of the heart rate and QT interval from 42 male and 11 female micominipigs [1, 3,5,9,10,16,18]. The new correction formulae made the slope of regression lines for the QT interval of total, male and female micominipigs more flat, as shown in Fig.…”

“…The QTc calculated by the correction formulae for each animal during the sinus rhythm is also plotted for reference (blue triangles). Figure 3 Evaluation of correction formulae by using the QT interval and RR interval obtained from our previous studies using 42 male and 11 female micominipigs [1, 3,5,8,9,15,17]. Linear regression analyses between the RR interval and QT interval (black triangles), and those between the RR interval and corrected QT interval (red circles) were performed for total (A), male (B) and female (C) animals.…”