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Heart rate dependent potentiation of QRS prolongations can be detected in standard dog telemetry studies
Abstracts
the costs of bringing unsafe compounds to the clinic, it is critical to try to predict the possible outcome in man. For a set of 22 compounds for different therapeutic indications, we performed a comparison of studies in man with preclinical in vivo cardiovascular dog studies. In this analysis we focused on potential correlations for some ECG (PQ, QRS, QT and QTc) and basic hemodynamic parameters (blood pressure and heart rate). Data include conscious and/or anesthetized dog preclinical studies and clinical Phase 1 trials (not all designed for sensitive hemodynamic and ECG analysis) and expressed as vehicle corrected percent change versus baseline values. Nevertheless, we explored whether these studies can be used in translational science. Our conclusions show clear opportunities for such an approach but also the need for clear and common criteria of relevant effect size both for clinical as preclinical trials. doi:10.1016/j.vascn.2012.08.055
Heart rate dependent potentiation of QRS prolongations can be detected in standard dog telemetry studies Caroline Cros, Jackie Moors, Matthew Skinner, Jean-Pierre Valentin, Pierre Lainee Safety Assessment UK, AstraZeneca R&D, Macclesfield, United Kingdom Drugs slowing conduction of the cardiac action potential and therefore prolonging the QRS interval by blocking the sodium current (INa) may carry pro-arrhythmic risks. Due to the frequency-dependent block of INa, it was shown that increases in heart rate (HR) potentiated the QRS prolongation induced by Na block in man (Sadanaga et al., 1993). This study assesses whether activity-related changes in HR occurring during standard dog telemetry studies can be used to increase the QRS prolongation induced by class I anti-arrhythmic compounds. Four telemetered dogs were orally dosed with quinidine (QUI: 25 mg/kg; class Ia), mexiletine (MEX: 10 mg/kg; class Ib) and flecainide (FLE: 20 mg/kg; class Ic). QRS duration was determined at rest but also prior to and at the plateau of each acute increase in HR (N60 bpm), and averaged over each hour period during 4 h post-dose. Percentage changes are shown as differences vs. time-matched vehicle effects. All compounds induced increases in QRS duration (Emax 13%, 5% and 20% for QUI, MEX and FLE respectively). The increase in QRS duration was enhanced at peak HR with an additional effect of + 2% for QUI, + 5% MEX and +5% for FLE. This study shows that periods of activity, usually rejected from routine analysis focused on QT prolongation, can be used to sensitize the detection of QRS prolongation. This could prove useful when subrelevant effects are detected and could also be used as spontaneous stress-tests for other aspects such as cardiac contractility. doi:10.1016/j.vascn.2012.08.056
Assessment of left ventricular dP/dtmax in telemetry studies: Essential or excessive? Matt Skinner, Pierre Lainee, Jean-Pierre Valentin, Jackie Moors
175
detectable changes in blood pressure (BP) and/or heart rate (HR). Another reason is that indices of contractility such as dP/dtmax are also affected by changes in preload, afterload and HR and therefore are complex to interpret. We reviewed 59 telemetry studies performed over the last 5 yrs in conscious dogs or monkeys in which left ventricular pressure recordings were made and examined the effects on BP, HR and dP/dtmax. A significant change in dP/dtmax was reported in 40 studies (68%). In 77% of these studies, the change in dP/dtmax was accompanied, or preceded at lower doses, by a significant change in HR whereas in 50% of these studies a change in BP was evident. However, in 18% of these studies, the change in dP/ dtmax occurred in the absence of any effects on BP or HR. Also, in an additional 5% of these studies, changes in dP/dtmax were the first cardiovascular effects detected, occurring at lower doses than eventual changes in BP or HR. These data show that in some studies, changes in dP/dtmax occur in the absence of changes in BP and HR supporting the routine use of this parameter in safety testing. In the remaining studies the changes in dP/dtmax must be interpreted in an integrated fashion taking into account effects on other determinants. doi:10.1016/j.vascn.2012.08.057
3-Model characterization of the relation between cardiac repolarization and temperature in guinea pig Morten Laursen, Anders B. Lassen, Olle Åkerlund, Rikke B. Strange Hansen, Tina Christensen, Joan Christiansen, Tomas Mow H. Lundbeck A/S, Copenhagen, Denmark In dog and minipig, temperature changes linearly affect cardiac repolarization. Since the guinea pig is commonly used for assessing effects on repolarization we examined the relation between repolarization and temperature in guinea pigs in 3 models: papillary muscle, Langendorff heart and anesthetized animals. In a range from 34 °C to 41 °C there was a negative correlation between temperature and repolarization both in vivo and ex vivo. In the isolated papillary muscle the slope of the APD90/ temperature relation was −7.8 ms/°C. In the isolated Langendorff heart the slope of the QT/temperature relation was −7.95 ms/°C. In the anesthetized animals the slope of the QTc/temperature relation was − 12.4 ms/°C after Bazett correction and − 6.1 ms/°C after individual correction. Compared to recently published in vivo guinea pig data (SPS 2010), we found a less steep correlation between repolarization and temperature when applying individual QT correction. However, using Bazett correction the slopes were similar to those data. Generally, individual formulas were very good at correcting for heart rate, whereas Bazett correction did not completely eliminate the effect of heart rate. This is supported by our findings in paced preparations, where rate-dependent changes are not a confounding factor: the ex vivo slope data are comparable to our individually corrected in vivo slope data. Our results confirm the importance of monitoring temperature when evaluating repolarization and show that temperature-dependence of repolarization is similar ex vivo and in vivo. Furthermore, individual heart rate correction of QT intervals is a superior method compared to Bazett correction.
Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, UK
doi:10.1016/j.vascn.2012.08.058
There is no regulatory requirement for assessment of cardiac contractility in safety pharmacology studies and also no consensus within the community on whether contractility per se should be measured routinely or on a case-by-case basis. One rationale for non-assessment is that any contractility changes should result in
Comparisons of Safety Pharmacology and general toxicology ECG's, and cardiovascular functional/pathology data Philip H. Millikena, Rhiannon C. Daviesb, Peter J.M. Clementsc, Bela A. Patela, Nick C. McMahona
the costs of bringing unsafe compounds to the clinic, it is critical to try to predict the possible outcome in man. For a set of 22 compounds for different therapeutic indications, we performed a comparison of studies in man with preclinical in vivo cardiovascular dog studies. In this analysis we focused on potential correlations for some ECG (PQ, QRS, QT and QTc) and basic hemodynamic parameters (blood pressure and heart rate). Data include conscious and/or anesthetized dog preclinical studies and clinical Phase 1 trials (not all designed for sensitive hemodynamic and ECG analysis) and expressed as vehicle corrected percent change versus baseline values. Nevertheless, we explored whether these studies can be used in translational science. Our conclusions show clear opportunities for such an approach but also the need for clear and common criteria of relevant effect size both for clinical as preclinical trials. doi:10.1016/j.vascn.2012.08.055
Heart rate dependent potentiation of QRS prolongations can be detected in standard dog telemetry studies Caroline Cros, Jackie Moors, Matthew Skinner, Jean-Pierre Valentin, Pierre Lainee Safety Assessment UK, AstraZeneca R&D, Macclesfield, United Kingdom Drugs slowing conduction of the cardiac action potential and therefore prolonging the QRS interval by blocking the sodium current (INa) may carry pro-arrhythmic risks. Due to the frequency-dependent block of INa, it was shown that increases in heart rate (HR) potentiated the QRS prolongation induced by Na block in man (Sadanaga et al., 1993). This study assesses whether activity-related changes in HR occurring during standard dog telemetry studies can be used to increase the QRS prolongation induced by class I anti-arrhythmic compounds. Four telemetered dogs were orally dosed with quinidine (QUI: 25 mg/kg; class Ia), mexiletine (MEX: 10 mg/kg; class Ib) and flecainide (FLE: 20 mg/kg; class Ic). QRS duration was determined at rest but also prior to and at the plateau of each acute increase in HR (N60 bpm), and averaged over each hour period during 4 h post-dose. Percentage changes are shown as differences vs. time-matched vehicle effects. All compounds induced increases in QRS duration (Emax 13%, 5% and 20% for QUI, MEX and FLE respectively). The increase in QRS duration was enhanced at peak HR with an additional effect of + 2% for QUI, + 5% MEX and +5% for FLE. This study shows that periods of activity, usually rejected from routine analysis focused on QT prolongation, can be used to sensitize the detection of QRS prolongation. This could prove useful when subrelevant effects are detected and could also be used as spontaneous stress-tests for other aspects such as cardiac contractility. doi:10.1016/j.vascn.2012.08.056
Assessment of left ventricular dP/dtmax in telemetry studies: Essential or excessive? Matt Skinner, Pierre Lainee, Jean-Pierre Valentin, Jackie Moors
175
detectable changes in blood pressure (BP) and/or heart rate (HR). Another reason is that indices of contractility such as dP/dtmax are also affected by changes in preload, afterload and HR and therefore are complex to interpret. We reviewed 59 telemetry studies performed over the last 5 yrs in conscious dogs or monkeys in which left ventricular pressure recordings were made and examined the effects on BP, HR and dP/dtmax. A significant change in dP/dtmax was reported in 40 studies (68%). In 77% of these studies, the change in dP/dtmax was accompanied, or preceded at lower doses, by a significant change in HR whereas in 50% of these studies a change in BP was evident. However, in 18% of these studies, the change in dP/ dtmax occurred in the absence of any effects on BP or HR. Also, in an additional 5% of these studies, changes in dP/dtmax were the first cardiovascular effects detected, occurring at lower doses than eventual changes in BP or HR. These data show that in some studies, changes in dP/dtmax occur in the absence of changes in BP and HR supporting the routine use of this parameter in safety testing. In the remaining studies the changes in dP/dtmax must be interpreted in an integrated fashion taking into account effects on other determinants. doi:10.1016/j.vascn.2012.08.057
3-Model characterization of the relation between cardiac repolarization and temperature in guinea pig Morten Laursen, Anders B. Lassen, Olle Åkerlund, Rikke B. Strange Hansen, Tina Christensen, Joan Christiansen, Tomas Mow H. Lundbeck A/S, Copenhagen, Denmark In dog and minipig, temperature changes linearly affect cardiac repolarization. Since the guinea pig is commonly used for assessing effects on repolarization we examined the relation between repolarization and temperature in guinea pigs in 3 models: papillary muscle, Langendorff heart and anesthetized animals. In a range from 34 °C to 41 °C there was a negative correlation between temperature and repolarization both in vivo and ex vivo. In the isolated papillary muscle the slope of the APD90/ temperature relation was −7.8 ms/°C. In the isolated Langendorff heart the slope of the QT/temperature relation was −7.95 ms/°C. In the anesthetized animals the slope of the QTc/temperature relation was − 12.4 ms/°C after Bazett correction and − 6.1 ms/°C after individual correction. Compared to recently published in vivo guinea pig data (SPS 2010), we found a less steep correlation between repolarization and temperature when applying individual QT correction. However, using Bazett correction the slopes were similar to those data. Generally, individual formulas were very good at correcting for heart rate, whereas Bazett correction did not completely eliminate the effect of heart rate. This is supported by our findings in paced preparations, where rate-dependent changes are not a confounding factor: the ex vivo slope data are comparable to our individually corrected in vivo slope data. Our results confirm the importance of monitoring temperature when evaluating repolarization and show that temperature-dependence of repolarization is similar ex vivo and in vivo. Furthermore, individual heart rate correction of QT intervals is a superior method compared to Bazett correction.
Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, UK
doi:10.1016/j.vascn.2012.08.058
There is no regulatory requirement for assessment of cardiac contractility in safety pharmacology studies and also no consensus within the community on whether contractility per se should be measured routinely or on a case-by-case basis. One rationale for non-assessment is that any contractility changes should result in
Comparisons of Safety Pharmacology and general toxicology ECG's, and cardiovascular functional/pathology data Philip H. Millikena, Rhiannon C. Daviesb, Peter J.M. Clementsc, Bela A. Patela, Nick C. McMahona