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Age related changes in cardiovascular measurements in beagle dogs
Abstracts
Poster No: 103 Age related changes in cardiovascular measurements in beagle dogs Giuseppina Iacono a, Kevin Norton a, Helen Penton a, Anne Bouchard b, Dany Salvail b a b
Charles River Laboratories, Montreal, Canada IPS Therapeutique, Sherbrooke, Qc, Canada
The human cardiovascular (CV) system is known to change physiologically during development. Compounds have been shown to have different electrocardiographic effects in juveniles vs. adults. Current development strategies use adult models to profile pediatric drugs. The objective of this study was to correlate in-vivo and ex-vivo changes in drug effects in dogs ranging from 2 to 6 months of age. Whole hearts were excised from immature dogs, with continuous ex vivo recording of ECG, monophasic action potential (MAP) and left ventricular pressure (LVP), whilst in vivo ECG measurements of HR, PR, QRS, QT and QTc Van der Waters were recorded. Changes in repolarisation kinetics were monitored following exposure to E-4031, an IKr (hERG in humans) inhibitor and Chromanol 293B, an IKs (KVLQT1) inhibitor. E-4031 (1 mg/kg)-induced QTc interval prolongation was not age-dependent, however, E-4031 (equivalent concentration)-induced QTc interval prolongation) decreased with age ex vivo. E-4031-induced IKr inhibition also caused an age-dependent reduction in the prolongation of MAPs in 2-mo old to 6-mo old hearts. Chromanol 293b (1 μM) prolonged the ex vivo QT interval, suggesting an age-dependent increase in IKs channel expression. This is in contrast to human juvenils in which IKr is generally fully expressed. Our findings suggest that consideration be given to the study of drugs in a juvenile canine safety CV system model when they are intended for use in human juveniles. doi:10.1016/j.vascn.2011.03.109
Poster No: 104 Exploratory cardiovascular safety pharmacology in the lead-optimization of novel small molecule kinase inhibitors Michael Flagella, Lewis Gazzard, Jason Halladay, Ryan Yokogawa, Lisa Wong, Joe Lubach, Beth Blackwood, Shiva Malek, Donna Dambach
e31
monkeys identified minor, transient blood pressure decreases at therapeutic exposures, thus validating our approach. Coupled with repeat-dose safety studies, a lead candidate compound with minimal cardiac effects was nominated for IND-enabling studies. doi:10.1016/j.vascn.2011.03.110
Poster No: 105 Elucidation of cardiovascular effects mediated by blockade of the PI3K/mTOR/Akt pathway using selective inhibitors Lisa M. Nottebaum, Michelle D. Hemkens, Eileen Blasi, Julie V. Selkirk, Aileen D. McHarg Pfizer, Inc San Diego, CA USA The PI3K/mTOR/AKT pathway is implicated in the growth and proliferation of cancer cells and so inhibition of this pathway may be beneficial in the treatment of cancer. Literature data however, suggest that inhibitors of this pathway may also have cardiovascular effects. The goal of this study was to evaluate the cardiovascular effects mediated by this pathway using differentially selective inhibitors: a dual inhibitor of mTOR/ PI3K, a selective mTOR inhibitor and a nonselective pan inhibitor of PI3K. These inhibitors were profiled in rat isolated heart (IH), rat isolated aorta and resistance vessels, and in conscious rat telemetry studies. In vitro data generated using rat IH demonstrated a concentration dependent increase in contractility with the dual PI3K/mTOR inhibitor whereas the pan PI3K inhibitor produced a small increase in contractility and the selective mTOR inhibitor had no effect. In the rat telemetry, administration of both the dual and pan PI3K inhibitors produced an increase in blood pressure and a decrease in heart rate whereas no change in BP or HR was observed after administration of the mTOR selective inhibitor. Pharmacokinetic data demonstrate that free plasma levels achieved in these studies were above the cell-based IC50 for AKT phosphorylation. Studies are ongoing to determine if inhibition of the PI3K pathway results in direct effects on the vasculature. In summary, current data suggest that inhibition of the PI3K pathway results in hemodynamic and contractility effects whereas inhibition of the mTOR pathway has no effect. doi:10.1016/j.vascn.2011.03.111
Genentech, South San Francisco, CA USA Poster No: 106 Early prediction of potential cardiac liabilities and selection of molecules without these liabilities in the research phase will enable an overall decrease in compound attrition at later stages of drug development. During the early lead optimization phase of novel small molecule kinase inhibitors, we observed acute, lethal toxicities in some, but not all, structurally-similar molecules at sub-efficacious exposures. These toxicities were consistent with functional changes to neuromuscular or cardiovascular systems, and were not attributable to inhibition of the intended target kinase. Overlapping patterns of significant off-target inhibition (muscarinic, GABAa GPCRs and acetylcholinesterase) provided insight into the observed toxicities. Our approach integrated cardiac safety pharmacology testing (e.g. ex vivo Langendorff preparations and rodent telemetry systems) into medicinal chemistry. We iteratively utilized in vitro receptor binding and functional assays with in vivo counter-screens to rank-order compounds with the lowest potential for cardiac safety liabilities. Efficacious, free-drug exposures were used to guide safety pharmacology experiments and to identify a lead candidate based on the best possible safety characteristics and margin. Studies in telemeterized
Ex-vivo investigation of aldosterone-induced endothelial dysfunction in the Rat Michelle D. Hemkens, Jonathan R. Heyen, Lisa Nottebaum, Qing Zong, Julie V. Selkirk, Aileen D. McHarg Global Safety Pharmacology, Pfizer Inc., La Jolla, CA, USA For potential diabetes therapies, a thorough preclinical cardiovascular safety evaluation is of the utmost importance. Endothelial dysfunction is one of the first indications of diabetic vascular complications, often preceding the symptoms of diabetes, and has pathology that stems from a wide variety of sources including endothelial damage. As such, a thorough testing funnel for diabetes compounds should include some method for de-risking endothelial damage. The question remains however, is there a sensitive yet resource-minimizing method for detection of such endothelial damage? The aim of this study was to use ex vivo tissue bath and myograph techniques to investigate vascular dysfunction using a
Poster No: 103 Age related changes in cardiovascular measurements in beagle dogs Giuseppina Iacono a, Kevin Norton a, Helen Penton a, Anne Bouchard b, Dany Salvail b a b
Charles River Laboratories, Montreal, Canada IPS Therapeutique, Sherbrooke, Qc, Canada
The human cardiovascular (CV) system is known to change physiologically during development. Compounds have been shown to have different electrocardiographic effects in juveniles vs. adults. Current development strategies use adult models to profile pediatric drugs. The objective of this study was to correlate in-vivo and ex-vivo changes in drug effects in dogs ranging from 2 to 6 months of age. Whole hearts were excised from immature dogs, with continuous ex vivo recording of ECG, monophasic action potential (MAP) and left ventricular pressure (LVP), whilst in vivo ECG measurements of HR, PR, QRS, QT and QTc Van der Waters were recorded. Changes in repolarisation kinetics were monitored following exposure to E-4031, an IKr (hERG in humans) inhibitor and Chromanol 293B, an IKs (KVLQT1) inhibitor. E-4031 (1 mg/kg)-induced QTc interval prolongation was not age-dependent, however, E-4031 (equivalent concentration)-induced QTc interval prolongation) decreased with age ex vivo. E-4031-induced IKr inhibition also caused an age-dependent reduction in the prolongation of MAPs in 2-mo old to 6-mo old hearts. Chromanol 293b (1 μM) prolonged the ex vivo QT interval, suggesting an age-dependent increase in IKs channel expression. This is in contrast to human juvenils in which IKr is generally fully expressed. Our findings suggest that consideration be given to the study of drugs in a juvenile canine safety CV system model when they are intended for use in human juveniles. doi:10.1016/j.vascn.2011.03.109
Poster No: 104 Exploratory cardiovascular safety pharmacology in the lead-optimization of novel small molecule kinase inhibitors Michael Flagella, Lewis Gazzard, Jason Halladay, Ryan Yokogawa, Lisa Wong, Joe Lubach, Beth Blackwood, Shiva Malek, Donna Dambach
e31
monkeys identified minor, transient blood pressure decreases at therapeutic exposures, thus validating our approach. Coupled with repeat-dose safety studies, a lead candidate compound with minimal cardiac effects was nominated for IND-enabling studies. doi:10.1016/j.vascn.2011.03.110
Poster No: 105 Elucidation of cardiovascular effects mediated by blockade of the PI3K/mTOR/Akt pathway using selective inhibitors Lisa M. Nottebaum, Michelle D. Hemkens, Eileen Blasi, Julie V. Selkirk, Aileen D. McHarg Pfizer, Inc San Diego, CA USA The PI3K/mTOR/AKT pathway is implicated in the growth and proliferation of cancer cells and so inhibition of this pathway may be beneficial in the treatment of cancer. Literature data however, suggest that inhibitors of this pathway may also have cardiovascular effects. The goal of this study was to evaluate the cardiovascular effects mediated by this pathway using differentially selective inhibitors: a dual inhibitor of mTOR/ PI3K, a selective mTOR inhibitor and a nonselective pan inhibitor of PI3K. These inhibitors were profiled in rat isolated heart (IH), rat isolated aorta and resistance vessels, and in conscious rat telemetry studies. In vitro data generated using rat IH demonstrated a concentration dependent increase in contractility with the dual PI3K/mTOR inhibitor whereas the pan PI3K inhibitor produced a small increase in contractility and the selective mTOR inhibitor had no effect. In the rat telemetry, administration of both the dual and pan PI3K inhibitors produced an increase in blood pressure and a decrease in heart rate whereas no change in BP or HR was observed after administration of the mTOR selective inhibitor. Pharmacokinetic data demonstrate that free plasma levels achieved in these studies were above the cell-based IC50 for AKT phosphorylation. Studies are ongoing to determine if inhibition of the PI3K pathway results in direct effects on the vasculature. In summary, current data suggest that inhibition of the PI3K pathway results in hemodynamic and contractility effects whereas inhibition of the mTOR pathway has no effect. doi:10.1016/j.vascn.2011.03.111
Genentech, South San Francisco, CA USA Poster No: 106 Early prediction of potential cardiac liabilities and selection of molecules without these liabilities in the research phase will enable an overall decrease in compound attrition at later stages of drug development. During the early lead optimization phase of novel small molecule kinase inhibitors, we observed acute, lethal toxicities in some, but not all, structurally-similar molecules at sub-efficacious exposures. These toxicities were consistent with functional changes to neuromuscular or cardiovascular systems, and were not attributable to inhibition of the intended target kinase. Overlapping patterns of significant off-target inhibition (muscarinic, GABAa GPCRs and acetylcholinesterase) provided insight into the observed toxicities. Our approach integrated cardiac safety pharmacology testing (e.g. ex vivo Langendorff preparations and rodent telemetry systems) into medicinal chemistry. We iteratively utilized in vitro receptor binding and functional assays with in vivo counter-screens to rank-order compounds with the lowest potential for cardiac safety liabilities. Efficacious, free-drug exposures were used to guide safety pharmacology experiments and to identify a lead candidate based on the best possible safety characteristics and margin. Studies in telemeterized
Ex-vivo investigation of aldosterone-induced endothelial dysfunction in the Rat Michelle D. Hemkens, Jonathan R. Heyen, Lisa Nottebaum, Qing Zong, Julie V. Selkirk, Aileen D. McHarg Global Safety Pharmacology, Pfizer Inc., La Jolla, CA, USA For potential diabetes therapies, a thorough preclinical cardiovascular safety evaluation is of the utmost importance. Endothelial dysfunction is one of the first indications of diabetic vascular complications, often preceding the symptoms of diabetes, and has pathology that stems from a wide variety of sources including endothelial damage. As such, a thorough testing funnel for diabetes compounds should include some method for de-risking endothelial damage. The question remains however, is there a sensitive yet resource-minimizing method for detection of such endothelial damage? The aim of this study was to use ex vivo tissue bath and myograph techniques to investigate vascular dysfunction using a