Safety Pharmacology Society Webinar:

Cardiac Physiology and Chronobiology

Maxim Soloviev, MD, PhD, DSP Incyte Corporation, Wilmington, DE

Overview

 Basics of conductive system  ECG 101  Diurnal variability in different species

Cardiac conduction system

 Impulse initiated by the Sinus Node.  It travels to the atriums and to the Atrioventricular (AV) Node located between the chambers  The AV Node slows the impulse down and passes it through to the AV Bundle (or )  Bundle of His divides itself into two tracts through the ventricles and the , which stimulate muscle of the ventricles

ECG and Cardiac Activity

 Electrocardiogram (ECG) is a representation of the heart's electrical activity  The P wave, represents atrial depolarization  The QRS complex represents ventricular depolarization  The ST segment represents the repolarization of the ventricles  The QT interval represents ventricular depolarization and repolarization

AV Node Normal ECG

Normal duration and amplitude of ECG waves, complexes, and segments is variable in different species E.g. QT/RR ratio in normal conditions human > monkey > dog

How to Think about Heart Rhythm

Electrical Impulse Formation

Site of Origin Rate Regularity

•Sinus Node •Normal •Regular • •Fast •Irregular •AV node •Slow •

•Consistency Sinus arrhythmia  Common finding, more prominent in dogs

Sinus bradyarrhythmia  Common finding, more prominent in dogs, especially during night hours (vagal prevalence)

Sinus arrhythmia with ventricular escape complex  Less common finding, still can be observed in healthy animals

AV block

 First degree AV block – prolongation of PR interval  Second degree AV block – Type 1 (aka Mobitz 1 or Wenckebach): Progressive prolongation of PR interval with dropped beats – Type 2 (aka Mobitz 2 or Hay): PR interval remains unchanged prior to the P wave which suddenly fails to conduct to the ventricles.  Third degree AV block, also known as complete heart block, condition when impulse generated in the sinus node does not propagate to the ventricles 2nd Degree AV Block, Type 2  Common finding in healthy animals, more frequent in dogs 3rd degree AV block  Impulse generated in the sinus node, conducts to atria but does not propagate to the ventricles  If impulse for ventricles generated at AV node or His Bundle before bifurcation, QRS complex can be of normal shape Single PVC  Ventricular cell may initiate an impulse and cause a premature ventricular contraction (PVC)  A single occurrence is seen quite often an does not cause any serious problems Multiple polytopic PVC  Abnormal finding, may suggest myocardial damage and/or issues with repolarization  Frequent PVC dramatically increase probability of polymorphic ventricular tachycardia aka Torsades de Pointes (TpD) Torsades de Pointes  Torsades de pointes (TdP) – is a polymorphic ventricular tachycardia that can cause sudden death  Although uncommon, TPD is one of the most severe cardiac side effects Chronopharmacology

Chronokinetics of Indomethacin Other examples: (Human data) • Amitriptylin • Diasepam • • Propranolol • Verapamil • Nidedipin • Theophyllin …

Clench et al., 1981 Chronopharmacology

Same amount of drug given at a different time of the days may result in different exposure (Cmax, Tmax, AUC…) - Chronopharmacokynetics

Same amount of drug given at a different time of the days may result in different pharmacodynamic response - Chronopharmacodynamics

v. Mayersbach, 1976 Diurnal Variability in HR

Difference between nocturnal and diurnal species

Minipigs Sato et al, 1995; Soloviev at al, 2006; Stubban et al 2008 Diurnal Variability in BP

Minipigs Sato et al, 1995; Soloviev at al, 2006; Stubban et al 2008 Diurnal Variability in Temperature

Rat, activity

Rat, temperature

Minipigs Stubban et al 2008; Soloviev at al, 2003; Soloviev at al, 2006 Diurnal Variation of QT interval

300 Difference up to 32 msec (12.7%)

270

240

QT (msec) 210

180

150

60-70 70-80 80-90 90-100 100-110 110-120 120-130 130-140 140-150 150-160 160-170 170-180 180-190 (bpm)

NHP Light NHP Dark Dog Light Dog Dark Suggested Literature

 Authier, S et al., A cardiovascular monitoring system in conscious cynomolgus monkeys for regulatory safety pharmacology. Part 1: Non-pharmacological validation. J Pharmacol Toxicol Methods, 2007. 56: p. 115-121.  Brown AM Drugs, hERG and sudden death. (2004) Cell Calcium 35(6):543-547.  Detweiler, D.K. (1988). The mammalian electrocardiogram, in Comprehensive Electrocardiography: Theory and Practice in Health and Disease (MacFarlane, PW and Lawrie, T.D.V., eds.). Pergamon, New York.  Dubin D. Rapid Interpretation of EKG's. 2000.  Hamlin RL. How many ECG leads are required for in vivo studies in safety pharmacology? (2008) J Pharmacol Toxicol Methods. 57(3):161-8.  Gauvin DV et al (2006) Spontaneous cardiac arrhythmias recorded in three experimentally- and drug- naive laboratory species (canine, primate, swine) during standard pre-study screening. J Pharmacol Toxicol Methods. 59(2):57-61.  Gauvin, DV et al (2006). Electrocardiogram, hemodynamics, and core body temperatures of the normal freely moving cynomolgus monkey by remote radiotelemetry. J. Pharmacol. Toxicol.Methods 53(2):140–151. Suggested Literature  Leishman, D et al., Best practice in key nonclinical cardiovascular assessments in drug development: current recommendations from the SPS. J Pharmacol Toxicol Methods, 2012 May-Jun;65(3):93-101.  Lemmer B. Relevance for chronopharmacology in practical medicine. Semin Perinatol. 2000 Aug;24(4):280-90.  Lemmer B. Chronobiology, drug-delivery, and chronotherapeutics. Adv Drug Deliv Rev. 2007 Aug 31;59(9-10):825-7.  Markert, M., et al., Validation of the normal, freely moving Göttingen minipig for pharmacological safety testing. J Pharmacol Toxicol Methods, 2009. 60: p. 79-87.  Mayersbach H. (1976). Time – a key in experimental and practical medicine. Arch. Toxicol. 36 185– 216.  Sato, K. et al, Circadian and short-term variabilities in blood pressure and heart rate measured by telemetry in rabbits and rats. J Auton Nerv Syst, 1995. 54(3): p. 235-46.  Soloviev MV et al. (2006) Different species require different QT corrections. Cardiovascular Toxicology, 6(2): 145-157.  Soloviev MV et al. (2006). Variations in hemodynamic parameters and ECG in healthy conscious freely moving telemetrized beagle dogs. Cardiovasc. Toxicol. 6(1):51–62.  Tilley LP et al. Canine and Feline Cardiac Arrythmias Self Assesment. 1999. Thank you!

Questions?