QT PRODACT: In Vivo QT Assay in Anesthetized Dog for Detecting the Potential for QT Interval Prolongation by Human Pharmaceuticals

Tashibu, Hiroyuki; Miyazaki, Hiroyasu; Aoki, Kumiko; Akie, Yasuki; Yamamoto, Keiji

doi:10.1254/jphs.qt-a3

Cited by 41 publications

(22 citation statements)

References 48 publications

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“…Although significant changes in HR including marked increases in it were occasionally observed, they were not considered to be related to the treatment since the changes were transient and no significant effect on HR was observed in anesthetized dogs (17,18). There was no significant change in QRS duration.…”

Section: Summary Of Changes In Qtcf Intervalmentioning

confidence: 99%

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

et al. 2005

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Abstract. The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n = 4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma / serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals. Supplementary material (Appendix): available only at http://dx

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Section: Summary Of Changes In Qtcf Intervalmentioning

confidence: 99%

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

et al. 2005

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“…At such longer RR intervals, a plot of QT versus RR is almost flat, whereas the QT interval lengthened with an increase in RR interval at shorter RR intervals, suggesting that a logarithmic correction formula might be more suitable for a wide range of RR intervals. In anesthetized dogs, however, such severe bradycardia is not usually observed even when administering bradycardiac drugs (Tashibu et al, 2005). Therefore, Matsunaga's formula might show a poor fit in the present study because of the relative short range of RR intervals.…”

Section: Discussionmentioning

confidence: 67%

“…Fridericia's formula−division of the QT interval by the cube root of the RR interval-was effectively used in a large−scale QT assessment trial performed by JPMA QT PRODACT using isoflurane-anesthetized dogs (Tashibu et al, 2005). Although the group did not demonstrate the appropriateness of the formula scientifically, the study did detect the effects of clinically QT-prolonging and non-QT-prolonging drugs on QTcF interval with high accuracy.…”

Section: Discussionmentioning

confidence: 99%

“…However, in conscious animals, spontaneous physiological changes in hemodynamics dependent on posture or activity make the measurement of the QT interval generally more variable than in anesthetized animals. In addition, the Japan Pharmaceutical Manufacturers Association (JPMA) QT PRODACT suggests that a QT study using isoflurane-anesthetized dogs is more accurate to druginduced QT interval prolongation than one using conscious animals (Ando et al, 2005;Tashibu et al, 2005;Toyoshima et al, 2005). Halothane, an anesthetic used for anesthetized studies as well as isoflurane, would help detect the potential risk of drugs to prolong the QT interval with high sensitivity because it inhibits the human ether-a-go-go-related gene (hERG) channel (Li and Correa, 2002), the alpha subunit of rapidly activating delayed rectifier K + currents (I Kr ) mainly responsible for ventricular repolarization, and might potently reduce the repolarization reserve (Biliczki et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Qt-Rr Relationships and Suitable Qt Correction Formulas for Halothane-Anesthetized Dogs

et al. 2006

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-Several QT correction (QTc) formulas have been used for assessing the QT liability of drugs. However, they are known to under-and over-correct the QT interval and tend to be specific to species and experimental conditions. The purpose of this study was to determine a suitable formula for halothane-anesthetized dogs highly sensitive to drug-induced QT interval prolongation. Twenty dogs were anesthetized with 1.5% halothane and the relationship between the QT and RR intervals were obtained by changing the heart rate under atrial pacing conditions. The QT interval was corrected for the RR interval by applying 4 published formulas (Bazett, Fridericia, Van de Water, and Matsunaga); Fridericia's formula (QTcF = QT/RR 0.33 ) showed the least slope and lowest R 2 value for the linear regression of QTc intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. An optimized formula (QTcX = QT/RR 0.3879 ) is defined by analysis of covariance and represents a correction algorithm superior to Fridericia's formula. For both Fridericia's and the optimized formula, QT-prolonging drugs (d,l-sotalol, astemizole) showed QTc interval prolongation. A non-QT-prolonging drug (d,l-propranolol) failed to prolong the QTc interval. In addition, drug-induced changes in QTcF and QTcX intervals were highly correlated with those of the QT interval paced at a cycle length of 500 msec. These findings suggest that Fridericia's and the optimized formula, although the optimized is a little bit better, are suitable for correcting the QT interval in halothane-anesthetized dogs and help to evaluate the potential QT prolongation of drugs with high accuracy.

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“…Indeed, this effect may be due to the presence of ketoconazole because the serum level of terfenadine increased and the concentrations of metabolite decreased, which suggested that ketoconazole inhibited terfenadine metabolism [16]. Terfenadine at 0.3 mg/kg (iv) produced no effect on the QT interval, but at 1 and 3 mg/kg, it significantly prolonged the QT interval in dogs [24]. In guinea pigs, a 10 mg/kg intravenous infusion of terfenadine also resulted in QT prolongation, and an oral dose of terfenadine (50-60 mg) in combination with ketoconazole (200 mg/kg) caused immediate prolongation [11].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs

Rajput

Singh

Sharma

2010

Pharmacological Reports

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Abstract:Terfenadine and ketoconazole are the most widely used positive reference agents in non-clinical cardiac repolarization safety studies. The aim of the present study was to evaluate the effects of terfenadine, ketoconazole and their combination on QT prolongation using conscious guinea pigs. Conscious telemetered guinea pigs were orally administered terfenadine (50 mg/kg), ketoconazole (200 mg/kg) or a combination of the two, and effects on QT were recorded using a telemetry system. The QT correction was carried out with Bazett's formula to eliminate confounding effect of HR. Neither terfenadine nor ketoconazole produced any effect on the RR and QT intervals, QRS complex or heart rate (HR). However, a combination of terfenadine and ketoconazole significantly prolonged the RR and QT intervals and decreased HR in a time-dependent manner. This study demonstrated that the combination of terfenadine and ketoconazole produces QT prolongation in conscious telemetered guinea pigs.

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QT PRODACT: In Vivo QT Assay in Anesthetized Dog for Detecting the Potential for QT Interval Prolongation by Human Pharmaceuticals

Cited by 41 publications

References 48 publications

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

Qt-Rr Relationships and Suitable Qt Correction Formulas for Halothane-Anesthetized Dogs

Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs

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