QTc shortening with a new investigational cancer drug: a brief case study.
BACKGROUND
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).


CONCLUSIONS
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.
Himmel
Herbert M
HM
Safety Pharmacology, Bayer Schering Pharma AG, Wuppertal, Germany. herbert.himmel@bayerhealthcare.com
Hoffmann
Michael
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects*; D022062:Electrophysiologic Techniques, Cardiac; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009930:Organic Chemicals / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D015222:Sodium Channels / Q000378:metabolism
D000970:Antineoplastic Agents; C554305:BAY-79 compound; D015507:Drugs, Investigational; D051638:Ether-A-Go-Go Potassium Channels; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; C568320:SCN5A protein, human; D015222:Sodium Channels