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Heart rate correction of the QT interval: A nonparametric individualized approach
160
Journal of Pharmacological and Toxicological Methods 58 (2008) 147–178
effects on cardiac ion channels. In the future emphasis may shift to haemodynamic and inotropic assessment ideally in conscious animals removing the confounding effects of anaesthesia and acute surgery on contractility. As the dog model is impractical to evaluate contractility early a rat model is needed. This study evaluated pilocarpine (30 µmol/kg) and dobutamine (300 µg/kg) in anaesthetised and conscious rats. In anaesthetised experiments (with pentobarbitone), rats were instrumented with carotid, left ventricular and jugular catheters. In conscious experiments, rats were previously instrumented under anaesthesia with catheters in the left ventricle and a jugular vein and subcutaneous ECG electrodes. Both compounds increased myocardial contractility as assessed by left ventricular dP/dt max. Dobutamine's inotropic response which is considered mediated via direct cardiac ß1-adrenoceptor activation was unaffected by anaesthesia. Whereas, pilocarpine's inotropic response which is considered mediated via opposing indirect positive sympathomimetic and direct negative muscarinic inotropic effects differed. In conscious rats, the increase in contractility was stable and persisted long after the end of infusion. In contrast, in anaesthetised rats the inotropic effect was transientory. In conclusion, the conscious model may be more appropriate to investigate the early potential inotropic effect of NCEs without confounding anaesthetic effects. doi:10.1016/j.vascn.2008.05.059
Aims: The QT interval correction for heart rate changes is investigated. The dependence of the QT interval on the RR one is described by means of a flexible model-free nonparametric approach. The benefits of individualized correction formulas are also assessed. Materials: The telemetric technique was used to acquire data on 19 dogs. Animals were implanted at least 4 weeks before data acquisition with DSI transmitters. Data were acquired and analyzed with Notocord-hem software. 24-hour data were used to cover the widest range possible of heart rates (RR duration). QT and RR intervals were checked manually. The samples per subject ranged from 60 to 533. Methods: The new nonparametric method uses a regularization approach to fit the QT-RR data. Results were expressed as average root mean square error (RMSE) between the measured and predicted QT interval over test sets. Results and Discussion: The new correction method was compared with four other formulas: Bazett's, Fridericia's, linear model, power model. On the overall population the nonparametric correction is generally better. The nonparametric method yielded the best result also when individualized correction formulas were applied. The QT predictions provided by population-trained schemes were compared with predictions provided by individualized ones. Using the nonparametric approach, the individualized correction yielded an average RMSE improvement of over 30%. The adoption of individualized QT correction is in accordance with recommendations by the Int. Conf. on Harmonization (www.fda.gov/cder/ guidance/6378dft.htm).
Sotalol as positive control for IKr block in HEK-293 cells and for QT prolongation in conscious monkeys and dogs
doi:10.1016/j.vascn.2008.05.061
Valeria Perego, Claudio Arrigoni, Cristiano Cavazzoli (Accelera, Nerviano Medical Sciences, V. de L. Pasteur, 10 Nerviano (MI) 20014, Italy)
Cardiovascular safety evaluations assessment in exercise stress and heart failure models
Sotalol is a nonselective ß-adrenergic receptor antagonist that also prolongs cardiac action potential and the QT interval of the ECG by inhibiting the delayed rectifier K+ current IKr. It is therefore a suitable drug to test the sensitivity of in vitro and in vivo protocols for studying QT prolongation liabilities. The effect of sotalol on the IKr channel was studied in HEK-293 cells at concentrations of 10, 50, 100 and 500 µM. Cynomolgus monkeys and beagle dogs (n = 4 each) were treated orally with sotalol at doses of 3, 10 and 30 mg/kg. ECG waveforms were collected up to 24 h after treatment from chronically implanted, conscious, freely moving animals. The same animals were dosed again at the same doses for determination of systemic exposure. The IC50 of sotalol for blocking the IKr current resulted to be 431 µM. In both dogs and monkeys, sotalol oral administration caused a dose-related prolongation of the corrected QT (QTca, covariate analysis correction) at all doses in monkeys and from the dose of 10 mg/kg in dogs. The mean maximum prolongation was 11, 19, 50 and 58 msec in dogs and 8, 31, 76 and 141 msec in monkeys following doses of 0, 3, 10 and 30 mg/kg, respectively. Peak sotalol plasma levels (Cmax) following oral administration were 1335, 4648 and 8580 ng/mL in dogs and 922, 3120 and 7565 ng/mL in monkeys at doses of 3, 10 and 30 mg/kg, respectively. In conclusion, ECG collection in conscious dogs and monkeys with telemetry has proven a sensitive and suitable model to study QT prolongation liabilities by new drugs.
Craig R. Hassler b, Matthew Coffeeb, Michael Hawk b, Michael Stonerook b, Matthew Ellinger b, Thomas Vincib, Brandon Woodb, Robert Lordob, Robert Hamlina (Battelle and The Ohio State University, USA) (Columbus, Ohio, USA)
doi:10.1016/j.vascn.2008.05.060 Heart rate correction of the QT interval: A nonparametric individualized approach G. Grecoa, A. Russua, C. Arrigonib, P. Magnia, G. De Nicolaoa, M. Rocchettib (Universitâ di Pavia, Italy) (Nerviano Medical Sciences, Nerviano, Italy)
Pre-clinical cardiac safety studies are typically conducted in healthy sedentary young research animals. However, drugs are typically not administered only to healthy or sedentary people. Orthostatic hypotension and exercise intolerance are adverse effects noted during clinical trials. Thus, animal models more relevant to the treatment population may predict potential liabilities of a candidate compound. Exercise, a documented stressor of the cardiovascular and pulmonary systems in healthy or cardiac compromised animals, may be useful to amplify potential adverse or beneficial effects of a test article. A treadmill exercised dog model was used to evaluate the cardiovascular effects of two commonly used heart failure drugs. Enalapril (E) ACE inhibitor 1.0 mg/kg and Carvedilol (C) non-selective beta-blocker 1.0 mg/kg, C + E, and placebo were evaluated and during treadmill exercise in normal dogs and dogs with pacemaker-induced heart failure (HF). Heart rates (HR) were not different from placebo (P) in normal dogs (ND) but were lower in heart failure dogs (HF) for C and C + E. Contractility (dP/dT max) during exercise (EX) in ND was decreased as compared to P for C + E and increased for E. Contractility in HF dogs during EX was decreased for C and C + E. Mean arterial pressure (MAP) in (ND) decreased for C + E as compared to P during rest and EX but not in HF dogs. EX in normal and HF dogs unmasked test article-related cardiac alterations not evident during sedentary evaluations, which included differences in: inotropy, pressure, HR, and stress intolerance.
doi:10.1016/j.vascn.2008.05.062
Journal of Pharmacological and Toxicological Methods 58 (2008) 147–178
effects on cardiac ion channels. In the future emphasis may shift to haemodynamic and inotropic assessment ideally in conscious animals removing the confounding effects of anaesthesia and acute surgery on contractility. As the dog model is impractical to evaluate contractility early a rat model is needed. This study evaluated pilocarpine (30 µmol/kg) and dobutamine (300 µg/kg) in anaesthetised and conscious rats. In anaesthetised experiments (with pentobarbitone), rats were instrumented with carotid, left ventricular and jugular catheters. In conscious experiments, rats were previously instrumented under anaesthesia with catheters in the left ventricle and a jugular vein and subcutaneous ECG electrodes. Both compounds increased myocardial contractility as assessed by left ventricular dP/dt max. Dobutamine's inotropic response which is considered mediated via direct cardiac ß1-adrenoceptor activation was unaffected by anaesthesia. Whereas, pilocarpine's inotropic response which is considered mediated via opposing indirect positive sympathomimetic and direct negative muscarinic inotropic effects differed. In conscious rats, the increase in contractility was stable and persisted long after the end of infusion. In contrast, in anaesthetised rats the inotropic effect was transientory. In conclusion, the conscious model may be more appropriate to investigate the early potential inotropic effect of NCEs without confounding anaesthetic effects. doi:10.1016/j.vascn.2008.05.059
Aims: The QT interval correction for heart rate changes is investigated. The dependence of the QT interval on the RR one is described by means of a flexible model-free nonparametric approach. The benefits of individualized correction formulas are also assessed. Materials: The telemetric technique was used to acquire data on 19 dogs. Animals were implanted at least 4 weeks before data acquisition with DSI transmitters. Data were acquired and analyzed with Notocord-hem software. 24-hour data were used to cover the widest range possible of heart rates (RR duration). QT and RR intervals were checked manually. The samples per subject ranged from 60 to 533. Methods: The new nonparametric method uses a regularization approach to fit the QT-RR data. Results were expressed as average root mean square error (RMSE) between the measured and predicted QT interval over test sets. Results and Discussion: The new correction method was compared with four other formulas: Bazett's, Fridericia's, linear model, power model. On the overall population the nonparametric correction is generally better. The nonparametric method yielded the best result also when individualized correction formulas were applied. The QT predictions provided by population-trained schemes were compared with predictions provided by individualized ones. Using the nonparametric approach, the individualized correction yielded an average RMSE improvement of over 30%. The adoption of individualized QT correction is in accordance with recommendations by the Int. Conf. on Harmonization (www.fda.gov/cder/ guidance/6378dft.htm).
Sotalol as positive control for IKr block in HEK-293 cells and for QT prolongation in conscious monkeys and dogs
doi:10.1016/j.vascn.2008.05.061
Valeria Perego, Claudio Arrigoni, Cristiano Cavazzoli (Accelera, Nerviano Medical Sciences, V. de L. Pasteur, 10 Nerviano (MI) 20014, Italy)
Cardiovascular safety evaluations assessment in exercise stress and heart failure models
Sotalol is a nonselective ß-adrenergic receptor antagonist that also prolongs cardiac action potential and the QT interval of the ECG by inhibiting the delayed rectifier K+ current IKr. It is therefore a suitable drug to test the sensitivity of in vitro and in vivo protocols for studying QT prolongation liabilities. The effect of sotalol on the IKr channel was studied in HEK-293 cells at concentrations of 10, 50, 100 and 500 µM. Cynomolgus monkeys and beagle dogs (n = 4 each) were treated orally with sotalol at doses of 3, 10 and 30 mg/kg. ECG waveforms were collected up to 24 h after treatment from chronically implanted, conscious, freely moving animals. The same animals were dosed again at the same doses for determination of systemic exposure. The IC50 of sotalol for blocking the IKr current resulted to be 431 µM. In both dogs and monkeys, sotalol oral administration caused a dose-related prolongation of the corrected QT (QTca, covariate analysis correction) at all doses in monkeys and from the dose of 10 mg/kg in dogs. The mean maximum prolongation was 11, 19, 50 and 58 msec in dogs and 8, 31, 76 and 141 msec in monkeys following doses of 0, 3, 10 and 30 mg/kg, respectively. Peak sotalol plasma levels (Cmax) following oral administration were 1335, 4648 and 8580 ng/mL in dogs and 922, 3120 and 7565 ng/mL in monkeys at doses of 3, 10 and 30 mg/kg, respectively. In conclusion, ECG collection in conscious dogs and monkeys with telemetry has proven a sensitive and suitable model to study QT prolongation liabilities by new drugs.
Craig R. Hassler b, Matthew Coffeeb, Michael Hawk b, Michael Stonerook b, Matthew Ellinger b, Thomas Vincib, Brandon Woodb, Robert Lordob, Robert Hamlina (Battelle and The Ohio State University, USA) (Columbus, Ohio, USA)
doi:10.1016/j.vascn.2008.05.060 Heart rate correction of the QT interval: A nonparametric individualized approach G. Grecoa, A. Russua, C. Arrigonib, P. Magnia, G. De Nicolaoa, M. Rocchettib (Universitâ di Pavia, Italy) (Nerviano Medical Sciences, Nerviano, Italy)
Pre-clinical cardiac safety studies are typically conducted in healthy sedentary young research animals. However, drugs are typically not administered only to healthy or sedentary people. Orthostatic hypotension and exercise intolerance are adverse effects noted during clinical trials. Thus, animal models more relevant to the treatment population may predict potential liabilities of a candidate compound. Exercise, a documented stressor of the cardiovascular and pulmonary systems in healthy or cardiac compromised animals, may be useful to amplify potential adverse or beneficial effects of a test article. A treadmill exercised dog model was used to evaluate the cardiovascular effects of two commonly used heart failure drugs. Enalapril (E) ACE inhibitor 1.0 mg/kg and Carvedilol (C) non-selective beta-blocker 1.0 mg/kg, C + E, and placebo were evaluated and during treadmill exercise in normal dogs and dogs with pacemaker-induced heart failure (HF). Heart rates (HR) were not different from placebo (P) in normal dogs (ND) but were lower in heart failure dogs (HF) for C and C + E. Contractility (dP/dT max) during exercise (EX) in ND was decreased as compared to P for C + E and increased for E. Contractility in HF dogs during EX was decreased for C and C + E. Mean arterial pressure (MAP) in (ND) decreased for C + E as compared to P during rest and EX but not in HF dogs. EX in normal and HF dogs unmasked test article-related cardiac alterations not evident during sedentary evaluations, which included differences in: inotropy, pressure, HR, and stress intolerance.
doi:10.1016/j.vascn.2008.05.062