| QTc shortening with a new investigational cancer drug: a brief case study. | |
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MedLine Citation:
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PMID: 20570746 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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INTRODUCTION: BAY-79 is an inhibitor of receptor tyrosine kinases with high selectivity versus other kinases. Species scaling, complicated by nonlinear pharmacokinetics, predicted a C(max.u) of 36-178nmol/L at the human efficacious exposure. METHODS: Preclinical cardiovascular safety pharmacology studies assessed currents (hERG, I(Na)), action potential (AP, rabbit Purkinje fiber), hemodynamic/ECG parameters (anesthetized Beagle dogs, intravenous infusion), and proarrhythmic potential (rabbit Langendorff heart Screenit model). RESULTS: Both hERG K(+) current and hNav1.5 Na(+) current were inhibited with low potency (IC(20)>10micromol/L). Purkinje fiber APs remained unaffected at 10micromol/L, but at 100micromol/L displayed reverse use-dependent AP duration shortening (APD(90)-33% at 1Hz) and triangulation. Infusion of BAY-79 into anesthetized dogs was associated with moderate hemodynamic effects (increased heart rate and diastolic blood pressure, reduced stroke volume) and marked QTcV shortening (-25ms) starting at approximately 0.65micromol/L (unbound); QRS was not changed. Assessment of the proarrhythmic potential in the Screenit model showed effects (AP duration shortening, triangulation, instability, reduced coronary flow, slowed conduction) at > or =30micromol/L (0.5h/concentration) and at 3micromol/L with longer exposure (2.5h/concentration). DISCUSSION: BAY-79 at plasma concentrations slightly higher than those predicted to be therapeutically efficacious in humans is associated with QTc shortening in dogs but of unclear mechanistic basis. The QTc shortening associated proarrhythmic potential of BAY-79 together with other considerations finally resulted in an unfavorable risk-benefit assessment. |
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Authors:
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Herbert M Himmel; Michael Hoffmann |
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Publication Detail:
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Type: Journal Article Date: 2010-06-04 |
Journal Detail:
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Title: Journal of pharmacological and toxicological methods Volume: 62 ISSN: 1873-488X ISO Abbreviation: J Pharmacol Toxicol Methods Publication Date: 2010 Jul-Aug |
Date Detail:
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Created Date: 2010-08-30 Completed Date: 2010-12-23 Revised Date: 2011-07-22 |
Medline Journal Info:
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Nlm Unique ID: 9206091 Medline TA: J Pharmacol Toxicol Methods Country: United States |
Other Details:
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Languages: eng Pagination: 72-81 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Safety Pharmacology, Bayer Schering Pharma AG, Wuppertal, Germany. herbert.himmel@bayerhealthcare.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Action Potentials
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drug effects Animals Antineoplastic Agents / blood, pharmacology* Arrhythmias, Cardiac / chemically induced* Dogs Dose-Response Relationship, Drug Drug Evaluation, Preclinical Drugs, Investigational / pharmacology* Electrocardiography / drug effects* Electrophysiologic Techniques, Cardiac Ether-A-Go-Go Potassium Channels / metabolism Female HEK293 Cells Heart / drug effects*, physiology, physiopathology Humans Male Muscle Proteins / metabolism Organic Chemicals / administration & dosage, blood, pharmacology* Protein Kinase Inhibitors / administration & dosage, pharmacology Purkinje Fibers / drug effects, physiology Rabbits Sodium Channels / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/BAY-79 compound; 0/Drugs, Investigational; 0/Ether-A-Go-Go Potassium Channels; 0/Muscle Proteins; 0/Organic Chemicals; 0/Protein Kinase Inhibitors; 0/Sodium Channels; 0/sodium channel protein type 5 subunit alpha |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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