Safety Pharmacology Society Webinar:

Cardiac Physiology and Chronobiology

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

Overview

Basics of heart 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)

Bundle of His divides itself into two tracts through the ventricles and the Purkinje Fibers, 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

Site of Origin Rate Regularity

Electrical ImpulseFormation

•Sinus Node •Atrium •AV node •Ventricle

•Consistency

•Normal •Fast •Slow

•Regular •Irregular

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

Clench et al., 1981

Chronokinetics of Indomethacin (Human data)

Other examples: • Amitriptylin • Diasepam • Digoxin • Propranolol • Verapamil • Nidedipin • Theophyllin …

v. Mayersbach, 1976

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

Chronopharmacology

Diurnal Variability in HR Difference between nocturnal and diurnal species

Sato et al, 1995; Soloviev at al, 2006; Stubban et al 2008

Minipigs

Diurnal Variability in BP

Sato et al, 1995; Soloviev at al, 2006; Stubban et al 2008

Minipigs

Diurnal Variability in Temperature

Stubban et al 2008; Soloviev at al, 2003; Soloviev at al, 2006

Minipigs

Rat, activity

Rat, temperature

Diurnal Variation of QT interval

150

180

210

240

270

300

60-70

70-80

80-90

90-10

0

100-1

10

110-1

20

120-1

30

130-1

40

140-1

50

150-1

60

160-1

70

170-1

80

180-1

90

Heart Rate (bpm)

QT

(mse

c)

NHP Light NHP Dark Dog Light Dog Dark

Difference up to 32 msec (12.7%)

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?