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Comparison of two chronically-instrumented conscious dog models for assessment of cardiovascular function in safety pharmacology
e38
Abstracts
telemetry jackets did not impact the ability to accurately detect cardiovascular and neurobehavioral changes. The results demonstrate that an implanted telemetry device, a jacket containing inductive straps, and modified neurobehavioral assessment techniques can be used to successfully evaluate cardiovascular, respiratory and neurobehavioral function simultaneously in a single animal in the same study. doi:10.1016/j.vascn.2011.03.132
Poster No: 127 Developmental assessment of the electrocardiogram (ECG) in juvenile canines using external telemetry and moxifloxacin Cari M. Hudson, Marci L. Harter, Theodore J. Baird Safety Pharmacology & Neurobehavioral Sciences, MPI Research, Mattawan, MI, USA The use of juvenile animals on safety studies imparts insights to the potential toxicity of drugs intended for the pediatric human population and is required by regulatory agencies as part of the nonclinical safety evaluation of therapeutics intended for this population. One important function evaluated in juvenile studies is basic cardiac electrophysiology. Due to variability inherent in ECG determinations based on environment, technique, and other subjectspecific factors, it is essential that research facilities develop and maintain appropriate test methodologies and historical control data. The objectives of this study were two-fold: 1) to pilot procedures allowing periodic collection of ECGs using external telemetry from untreated juvenile to mature animals, and 2) to assess potential developmental differences in response to moxifloxacin, a drug which promotes hERG potassium channel mediated increase in QT/QTc. ECGs were collected monthly for 30 consecutive weeks utilizing the DSI JET system prior to and following administration of moxifloxacin or vehicle. Comparative data indicate considerably higher heart rates and correspondingly shorter durations of RR, PR, and QT intervals in untreated neonates. The magnitude of moxifloxacin-related cardiovascular effects was similar at each developmental stage evaluated. Results indicate that external telemetry is amenable to use in nearneonatal and developing juvenile canines, and that ventricular repolarization appears to be relatively uniformly affected by moxifloxacin administration, regardless of age. doi:10.1016/j.vascn.2011.03.133
Poster No: 128 Validation of JET™ (Jacketed External Telemetry) technology for ECG and blood pressure assessment in the dog Stephen C. Foote a, Jacob Holloway a, Adrianne Foote a, Peter Harris a, David Wolford b, Dingzhou Li c, Todd Wisialowski a, Jill Steidl a a
Global Safety Pharmacology, Pfizer Inc., Groton, CT, United States Bioanalytical Toxicology, Pfizer, Inc., Groton, CT, United States c Pharma Therapeutics Biostatistics, Pfizer Inc., Groton, CT, United States
with concurrent data acquisition was performed over five sessions of 7 h in duration and results indicate that 3 days is sufficient for animals to become accustomed to the jackets. Positive control agents were tested with JET in a crossover design and results were comparable to those generated with implantable telemetry. Doxazosin (0.3, 1, and 3 mg/kg), decreased blood pressure by 9, 11 and 15 mm Hg and increased heart rate by 6, 13 and 28 bpm, respectively. Moxifloxicin (10, 30, and 90 mg/ kg) increased QTc by 6, 16 and 31 ms, respectively. To further characterize JET sensitivity, a power analysis was performed on both 7 hour data generated using a crossover study design and 24 hour data generated using a repeat dose toxicology study design. These analyses demonstrate that JET is a highly sensitive model for characterization of drug-induced ECG and hemodynamic changes in acute or chronic studies. doi:10.1016/j.vascn.2011.03.134
Poster No: 129 Exploring filtering and correction factors in a standard dog cardiovascular model Monica R. Metea a, Thomas J. Vidmar b, Laurie J. Shellhammer a, Philip R. Atterson a a b
WIL Research Laboratories, LLC, Ashland, OH, United States BioSTAT Consultants, Portage, Michigan, United States
As beat-by-beat cardiovascular data collection is becoming a standard practice, the approaches for processing large amounts of data need to be reassessed. The aim of this study was to explore analysis methods of beat-by-beat data collected and processed using DSI Ponemah v4.8, and compare frequently used correction formulas. Methods: Eight telemetry-implanted beagle dogs were dosed in a Latin Square design with moxifloxacin at 5, 30, and 100 mg/kg and cardiovascular parameters were continuously acquired. Heart ratecorrected QT interval was calculated using Van de Water's, Fridericia's and Bazett's formulas or individual animal corrections and the differences from the zero reference for QT correction slopes computed. Four filtering paradigms for removal of noise and artifacts were compared using either automated filters or manually placed marks followed by interval-based filters applied for each method. Each filtering paradigm was analyzed with repeated-measure analysis of covariance. Results: 1) Statistical analysis conducted separately for each filtering method showed similarity of effects; 2) QTcV and QTcF showed the best correction for all dose groups (slopes not significantly different from zero). Individual correction factors did not perform better than the standard methods. 3) The QT prolongation corresponding to 80% power of detection confirmed that a 4 × 4 Latin Square design remains a suitable choice. doi:10.1016/j.vascn.2011.03.135
Poster No: 130
b
The aim of this work was to assess the quality and sensitivity of ECG and blood pressure data acquired using JET in single and multi-dose dog safety studies. A modified catheter was placed in the femoral artery of dogs for measurement of blood pressure with a rodent telemetry device (PA-C40). ECG (surface lead II configuration) and blood pressure signals were continuously measured in jacketed animals. Acclimation to jackets
Comparison of two chronically-instrumented conscious dog models for assessment of cardiovascular function in safety pharmacology Eric Delpy, Fabrice Infanti, Myriam Garreau, Christophe Drieu La Rochelle Biotrial Pharmacology, Non-Clinical Pharmacology Department, Rennes, France
Abstracts
Haemodynamic and ECG assessment is part of the safety pharmacology core battery as described in ICH S7A&B guidelines. The dog is well accepted as a predictive model of the cardiovascular (CV) effects of drugs in man. In conducting in vivo studies, conscious dogs conditioned to the laboratory environment are preferable to restraint or unconditioned animals. The objective of this study is to present and compare two models of chronically-instrumented conscious dogs (telemetry = TEL and indwelling catheters and probes = INDW) after administration of atenolol (AT), nicardipine and pimobendan. Dogs were anaesthetized for initial implantation of either a telemetry implant (D70-PCT, DSI) or fluid-filled catheters, a left ventricular micromanometer and aortic blood flow probe. Experiments were then performed in the kennel in freely-moving TEL animals or in the lab in INDW trained dogs lying on a table. Baseline values of CV parameters were almost similar between the two models. AT (3–30 mg/kg p.o.) induced a dose-dependant bradycardia, more pronounced and prolonged in time in INDW conscious dogs compared to TEL dogs; in addition in this model, AT induced a negative inotropic effect, a decrease in cardiac output and an increase in total peripheral resistance. Plasma concentration of AT determined in these experiments was well related to the dose. Nicardipine (3 mg/kg p.o.) decreased arterial pressure to a higher extent (magnitude and time) in INDW conscious dogs compared to TEL. In INDW dogs, this hypotensive effect is related to a decrease in TPR. Pimobendan (0.3 mg/kg p.o.) had almost no effect on AP and HR in both models but markedly increased myocardial contractility in INDW dogs. It is concluded that both chronically-instrumented conscious dog models are of interest in safety pharmacology. Advantages and disadvantages of each model will be presented. doi:10.1016/j.vascn.2011.03.136
Poster No: 131 The use of alternate QRS measurement methods to improve detection of propafenone-induced QRS prolongation Peter D. Harris a, Stephen C. Foote a, Dingzhou Li b, Bernard Fermini a, Jill Steidl a a b
Pfizer, Global Safety Pharmacology, Groton, CT USA Pfizer, PharmaTherapeutics Biostatistics, Groton, CT USA
The increased use of intracardiac or epicardial electrodes to obtain ECG recordings in various in vivo Safety Pharmacology cardiovascular models has led to QRS complexes that lack a well-defined J point. This has resulted in decreased precision in measurement of the end of the S wave and QRS interval duration. The purpose of this study was to evaluate a variety of alternate methods of QRS interval measurement using propafenone, a compound that increases QRS duration. Beagle dogs were dosed with propafenone (30 mg/kg, oral) followed by simultaneous ECG collection from epicardial telemetry leads and multiple surface leads. ECG data were analyzed with automated analysis software and by hand using digital calipers from a variety of lead vectors and from alternative end-of-S marking points. For each measurement, an average of 10 waves was used. Propafenone produced notable prolongation of the QRS interval. Our ability to measure QRS changes was greatest using V10 and V5 from the surface leads, whereas from the epicardial leads, precision of measurement of QRS interval changes was greatest when the end of the S wave was marked at the greatest negative deflection (trough). This trough measurement was shown to reduce the variability between wave complexes and thus increases sensitivity. In summary, accurate measurement of the QRS interval at a level needed to perform Safety studies can be obtained by using alternative leads or marker
e39
placement when a well defined J point is not present in the standard lead II ECG waveform. doi:10.1016/j.vascn.2011.03.137
Poster No: 132 Influence of emetic episodes on the assessment of cardiovascular parameters in dog telemetry studies Rikard Pehrson, Linnea Sjodin, Ahmad Al-Saffar AstraZeneca R&D, Södertälje, Sweden In dog cardiovascular safety studies of new drugs, emesis is commonplace. This study investigates if emesis per se results in changes in ECG, blood pressure and heart rate variability (HRV) in dogs. Lead II ECG and blood pressure were recorded in 4 male beagle dogs instrumented with telemetry. Recording took place in two separate sessions where dogs were given intragastrically either saline or CuSO4 (1%) to elicit an emetic response. ECG and blood pressure parameters were assessed in 1 minute intervals, obtained from periods with stable heart rate (thus not during active emesis). Following CuSO4, emetic episodes (1 to 8) occurred within 3–7 min after dosing in all dogs. Time between first and last emetic episodes (if more than one) was 3–14 min. Heart rate increased significantly up to 30 min after dosing, though heart rate tended to be increased up to 1.5 h after dosing (periods with stable heart rate). Blood pressure increased significantly in the vicinity of active emesis. There were no effects on QTcR interval (QT = a + b HR) whereas QTcV interval was significantly increased (mean increase +5%) from 30 to 75 min after dosing. There were no effects on QRS interval. HRV showed a long lasting increase in the high frequency component (vagal), on the expense of the low frequency component, from 0.25 to 2 h after dosing, despite no overt changes in overall heart rate (after 30 min). The dog with the most pronounced emetic response had the most marked changes in HRV. In conclusion, emesis per se causes long lasting effects in cardiovascular parameters with individual variability, indicating that emesis potentially masks drug related effects. HRV might be a better predictor than heart rate to identify the post-emetic periods.
doi:10.1016/j.vascn.2011.03.138
Poster No: 133 Characterization of spontaneous ventricular arrhythmias in telemetered beagle dogs Liguo Chi a, Joe Ng b, Carlen Audette c, Glenn Reinhart b a
Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Ridgefield CT, USA b General Pharmacology, Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Ridgefield CT, USA c Toxicology, Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Ridgefield CT, USA In the present study, we characterized the prevalence, frequency, hemodynamic impact and potential mechanisms of the onset of spontaneous ventricular arrhythmias (SVA) in telemetry implantinstrumented (ITS) beagle dogs. A method to efficiently identify SVA from a large data set and a strategy to effectively manage animals with SVA history also were established. ECG signals recorded during
Abstracts
telemetry jackets did not impact the ability to accurately detect cardiovascular and neurobehavioral changes. The results demonstrate that an implanted telemetry device, a jacket containing inductive straps, and modified neurobehavioral assessment techniques can be used to successfully evaluate cardiovascular, respiratory and neurobehavioral function simultaneously in a single animal in the same study. doi:10.1016/j.vascn.2011.03.132
Poster No: 127 Developmental assessment of the electrocardiogram (ECG) in juvenile canines using external telemetry and moxifloxacin Cari M. Hudson, Marci L. Harter, Theodore J. Baird Safety Pharmacology & Neurobehavioral Sciences, MPI Research, Mattawan, MI, USA The use of juvenile animals on safety studies imparts insights to the potential toxicity of drugs intended for the pediatric human population and is required by regulatory agencies as part of the nonclinical safety evaluation of therapeutics intended for this population. One important function evaluated in juvenile studies is basic cardiac electrophysiology. Due to variability inherent in ECG determinations based on environment, technique, and other subjectspecific factors, it is essential that research facilities develop and maintain appropriate test methodologies and historical control data. The objectives of this study were two-fold: 1) to pilot procedures allowing periodic collection of ECGs using external telemetry from untreated juvenile to mature animals, and 2) to assess potential developmental differences in response to moxifloxacin, a drug which promotes hERG potassium channel mediated increase in QT/QTc. ECGs were collected monthly for 30 consecutive weeks utilizing the DSI JET system prior to and following administration of moxifloxacin or vehicle. Comparative data indicate considerably higher heart rates and correspondingly shorter durations of RR, PR, and QT intervals in untreated neonates. The magnitude of moxifloxacin-related cardiovascular effects was similar at each developmental stage evaluated. Results indicate that external telemetry is amenable to use in nearneonatal and developing juvenile canines, and that ventricular repolarization appears to be relatively uniformly affected by moxifloxacin administration, regardless of age. doi:10.1016/j.vascn.2011.03.133
Poster No: 128 Validation of JET™ (Jacketed External Telemetry) technology for ECG and blood pressure assessment in the dog Stephen C. Foote a, Jacob Holloway a, Adrianne Foote a, Peter Harris a, David Wolford b, Dingzhou Li c, Todd Wisialowski a, Jill Steidl a a
Global Safety Pharmacology, Pfizer Inc., Groton, CT, United States Bioanalytical Toxicology, Pfizer, Inc., Groton, CT, United States c Pharma Therapeutics Biostatistics, Pfizer Inc., Groton, CT, United States
with concurrent data acquisition was performed over five sessions of 7 h in duration and results indicate that 3 days is sufficient for animals to become accustomed to the jackets. Positive control agents were tested with JET in a crossover design and results were comparable to those generated with implantable telemetry. Doxazosin (0.3, 1, and 3 mg/kg), decreased blood pressure by 9, 11 and 15 mm Hg and increased heart rate by 6, 13 and 28 bpm, respectively. Moxifloxicin (10, 30, and 90 mg/ kg) increased QTc by 6, 16 and 31 ms, respectively. To further characterize JET sensitivity, a power analysis was performed on both 7 hour data generated using a crossover study design and 24 hour data generated using a repeat dose toxicology study design. These analyses demonstrate that JET is a highly sensitive model for characterization of drug-induced ECG and hemodynamic changes in acute or chronic studies. doi:10.1016/j.vascn.2011.03.134
Poster No: 129 Exploring filtering and correction factors in a standard dog cardiovascular model Monica R. Metea a, Thomas J. Vidmar b, Laurie J. Shellhammer a, Philip R. Atterson a a b
WIL Research Laboratories, LLC, Ashland, OH, United States BioSTAT Consultants, Portage, Michigan, United States
As beat-by-beat cardiovascular data collection is becoming a standard practice, the approaches for processing large amounts of data need to be reassessed. The aim of this study was to explore analysis methods of beat-by-beat data collected and processed using DSI Ponemah v4.8, and compare frequently used correction formulas. Methods: Eight telemetry-implanted beagle dogs were dosed in a Latin Square design with moxifloxacin at 5, 30, and 100 mg/kg and cardiovascular parameters were continuously acquired. Heart ratecorrected QT interval was calculated using Van de Water's, Fridericia's and Bazett's formulas or individual animal corrections and the differences from the zero reference for QT correction slopes computed. Four filtering paradigms for removal of noise and artifacts were compared using either automated filters or manually placed marks followed by interval-based filters applied for each method. Each filtering paradigm was analyzed with repeated-measure analysis of covariance. Results: 1) Statistical analysis conducted separately for each filtering method showed similarity of effects; 2) QTcV and QTcF showed the best correction for all dose groups (slopes not significantly different from zero). Individual correction factors did not perform better than the standard methods. 3) The QT prolongation corresponding to 80% power of detection confirmed that a 4 × 4 Latin Square design remains a suitable choice. doi:10.1016/j.vascn.2011.03.135
Poster No: 130
b
The aim of this work was to assess the quality and sensitivity of ECG and blood pressure data acquired using JET in single and multi-dose dog safety studies. A modified catheter was placed in the femoral artery of dogs for measurement of blood pressure with a rodent telemetry device (PA-C40). ECG (surface lead II configuration) and blood pressure signals were continuously measured in jacketed animals. Acclimation to jackets
Comparison of two chronically-instrumented conscious dog models for assessment of cardiovascular function in safety pharmacology Eric Delpy, Fabrice Infanti, Myriam Garreau, Christophe Drieu La Rochelle Biotrial Pharmacology, Non-Clinical Pharmacology Department, Rennes, France
Abstracts
Haemodynamic and ECG assessment is part of the safety pharmacology core battery as described in ICH S7A&B guidelines. The dog is well accepted as a predictive model of the cardiovascular (CV) effects of drugs in man. In conducting in vivo studies, conscious dogs conditioned to the laboratory environment are preferable to restraint or unconditioned animals. The objective of this study is to present and compare two models of chronically-instrumented conscious dogs (telemetry = TEL and indwelling catheters and probes = INDW) after administration of atenolol (AT), nicardipine and pimobendan. Dogs were anaesthetized for initial implantation of either a telemetry implant (D70-PCT, DSI) or fluid-filled catheters, a left ventricular micromanometer and aortic blood flow probe. Experiments were then performed in the kennel in freely-moving TEL animals or in the lab in INDW trained dogs lying on a table. Baseline values of CV parameters were almost similar between the two models. AT (3–30 mg/kg p.o.) induced a dose-dependant bradycardia, more pronounced and prolonged in time in INDW conscious dogs compared to TEL dogs; in addition in this model, AT induced a negative inotropic effect, a decrease in cardiac output and an increase in total peripheral resistance. Plasma concentration of AT determined in these experiments was well related to the dose. Nicardipine (3 mg/kg p.o.) decreased arterial pressure to a higher extent (magnitude and time) in INDW conscious dogs compared to TEL. In INDW dogs, this hypotensive effect is related to a decrease in TPR. Pimobendan (0.3 mg/kg p.o.) had almost no effect on AP and HR in both models but markedly increased myocardial contractility in INDW dogs. It is concluded that both chronically-instrumented conscious dog models are of interest in safety pharmacology. Advantages and disadvantages of each model will be presented. doi:10.1016/j.vascn.2011.03.136
Poster No: 131 The use of alternate QRS measurement methods to improve detection of propafenone-induced QRS prolongation Peter D. Harris a, Stephen C. Foote a, Dingzhou Li b, Bernard Fermini a, Jill Steidl a a b
Pfizer, Global Safety Pharmacology, Groton, CT USA Pfizer, PharmaTherapeutics Biostatistics, Groton, CT USA
The increased use of intracardiac or epicardial electrodes to obtain ECG recordings in various in vivo Safety Pharmacology cardiovascular models has led to QRS complexes that lack a well-defined J point. This has resulted in decreased precision in measurement of the end of the S wave and QRS interval duration. The purpose of this study was to evaluate a variety of alternate methods of QRS interval measurement using propafenone, a compound that increases QRS duration. Beagle dogs were dosed with propafenone (30 mg/kg, oral) followed by simultaneous ECG collection from epicardial telemetry leads and multiple surface leads. ECG data were analyzed with automated analysis software and by hand using digital calipers from a variety of lead vectors and from alternative end-of-S marking points. For each measurement, an average of 10 waves was used. Propafenone produced notable prolongation of the QRS interval. Our ability to measure QRS changes was greatest using V10 and V5 from the surface leads, whereas from the epicardial leads, precision of measurement of QRS interval changes was greatest when the end of the S wave was marked at the greatest negative deflection (trough). This trough measurement was shown to reduce the variability between wave complexes and thus increases sensitivity. In summary, accurate measurement of the QRS interval at a level needed to perform Safety studies can be obtained by using alternative leads or marker
e39
placement when a well defined J point is not present in the standard lead II ECG waveform. doi:10.1016/j.vascn.2011.03.137
Poster No: 132 Influence of emetic episodes on the assessment of cardiovascular parameters in dog telemetry studies Rikard Pehrson, Linnea Sjodin, Ahmad Al-Saffar AstraZeneca R&D, Södertälje, Sweden In dog cardiovascular safety studies of new drugs, emesis is commonplace. This study investigates if emesis per se results in changes in ECG, blood pressure and heart rate variability (HRV) in dogs. Lead II ECG and blood pressure were recorded in 4 male beagle dogs instrumented with telemetry. Recording took place in two separate sessions where dogs were given intragastrically either saline or CuSO4 (1%) to elicit an emetic response. ECG and blood pressure parameters were assessed in 1 minute intervals, obtained from periods with stable heart rate (thus not during active emesis). Following CuSO4, emetic episodes (1 to 8) occurred within 3–7 min after dosing in all dogs. Time between first and last emetic episodes (if more than one) was 3–14 min. Heart rate increased significantly up to 30 min after dosing, though heart rate tended to be increased up to 1.5 h after dosing (periods with stable heart rate). Blood pressure increased significantly in the vicinity of active emesis. There were no effects on QTcR interval (QT = a + b HR) whereas QTcV interval was significantly increased (mean increase +5%) from 30 to 75 min after dosing. There were no effects on QRS interval. HRV showed a long lasting increase in the high frequency component (vagal), on the expense of the low frequency component, from 0.25 to 2 h after dosing, despite no overt changes in overall heart rate (after 30 min). The dog with the most pronounced emetic response had the most marked changes in HRV. In conclusion, emesis per se causes long lasting effects in cardiovascular parameters with individual variability, indicating that emesis potentially masks drug related effects. HRV might be a better predictor than heart rate to identify the post-emetic periods.
doi:10.1016/j.vascn.2011.03.138
Poster No: 133 Characterization of spontaneous ventricular arrhythmias in telemetered beagle dogs Liguo Chi a, Joe Ng b, Carlen Audette c, Glenn Reinhart b a
Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Ridgefield CT, USA b General Pharmacology, Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Ridgefield CT, USA c Toxicology, Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Ridgefield CT, USA In the present study, we characterized the prevalence, frequency, hemodynamic impact and potential mechanisms of the onset of spontaneous ventricular arrhythmias (SVA) in telemetry implantinstrumented (ITS) beagle dogs. A method to efficiently identify SVA from a large data set and a strategy to effectively manage animals with SVA history also were established. ECG signals recorded during