VALIDATION OF SAFETY PHARMACOLOGY ASSESSMENT OF CARDIOVASCULAR FUNCTION IN CONSCIOUS DOGS WITH TWO P

1
VALIDATION OF SAFETY PHARMACOLOGY ASSESSMENT OF
CARDIOVASCULAR FUNCTION IN CONSCIOUS DOGS WITH
TWO POSITIVE CONTROLS (SOTALOL AND IBUTILIDE)
Chen, Ya-Fei Lindeblad, Matthew Lyubimov,
AlexanderToxicology Research Laboratory,
University of Illinois at Chicago, 1940 W. Taylor
St, Chicago, IL 60612
ABSTRACT Drug-induced effects on the
QT-interval with the possibility of inducing
fatal arrhythmias have become a new challenge for
drug development and regulatory approval.
Antiarrhythmic class III drugs have been
associated with development of a polymorphic
ventricular tachycardia (PVT) known as torsades
de pointes. The purpose of this study was to
validate the method of safety pharmacology
assessment of cardiovascular function using two
class III agents, d,l-sotalol and ibutilide, in a
conscious telemetric canine model. The duration
of QT-interval has been used as the major
determinant of the risk of drug-induced PVT. A
telemetry transmitter (D70-PCT) from Data
Sciences International (DSI) was implanted
subcutaneously into the flank of each dog
following the standard surgical procedures. The
animals blood pressure, ECG, heart rate, body
temperature and locomotor activity were
continuously monitored for at least 24 hours
prior to and following a single bolus intravenous
dosing of saline (vehicle control). The
d,l-sotalol at 10 mg/kg or ibutilide at 0.15
mg/kg were injected intravenously three days
later. ECG waveforms and above cardiovascular
parameters were recorded simultaneously for at
least 24 hours following each drug
administration. The heart rate-adjusted QT
intervals (Fridericia correction QTcF) were
determined using the rate-correction formula in
DSI PhysiostatTM ECG analysis program. Both
sotalol and ibutilide significantly increased
QT-interval with similar pattern in the beagle
dogs. These data demonstrated that the assay is
capable of detecting relevant changes in
cardiovascular function in conscious beagle dogs.
This validated telemetry canine model and either
sotalol or ibutilide as a positive control can be
used to study the potential undesirable
pharmacodynamic effects of the test compounds on
QT-interval for accessing clinical benefits and
risks in accordance to the ICH safety
pharmacology S7B guideline.
Results

Materials and Methods Test System One male (
10 kg) and one female ( 8 kg) healthy Beagle dog
received from Marshall Farms were used. The dog
is a standard and accepted non-rodent species for
Safety Pharmacology studies. Animal
Preparation Data Sciences International (St.
Paul, MN) D70-PCT telemetry transmitter (Lead II
ECG and femoral artery) were implanted
subcutaneously under anesthesia by the UIC
veterinary personnel. The catheter for blood
pressure measurement was carefully inserted into
the femoral artery. The positive wire coil and
negative wire coil were placed into a muscle
tunnel and anchored to tissue on the left and
right lateral thorax, respectively. The animals
were allowed to recover for at least 7 days
following the surgical procedure. Dosing The
0.9 physiological saline (used as control
vehicle), two class III antiarrythmic agents
(used as positive control), d,l-sotalol (Sigma)
at 10 mg/kg or ibutilide (Sigma) at 0.15 mg/kg
were injected intravenously as a single bolus
after approximately 7 days washout period. The
ECG waveforms and cardiovascular parameters were
continuously recorded for at least 24 hours
following each administration. Data
Acquisition and Analysis For assessment of QT
interval prolongation, the ECG and other
cardiovascular evaluation data were recorded
continuously for at least 24 hours immediately
following the sotalol administration using DSI
canine telemetry system (Figure 1). Individual
animal plots of body temperature, blood pressure
(systolic, diastolic, and mean) and heart rate
were prepared using DSI DataquestARTTM data
analysis program. The heart rate-adjusted QT
interval (QTcF) was determined using the
rate-correction Fridericia formula in DSI
PhysioststTM ECG analysis program.
Figure 2 Example of data (MAP, HR, Temp and
ECG) recorded by DSI DATAQUEST ART system.

• Conclusions
• The ability of simultaneous data acquisition
  during several periods of 24 hours continuous
  data collection was successfully demonstrated in
  UIC-TRL settings.
• The suitability of a Data Science International
  software package for analysis of the
  cardiovascular telemetry measurements (including
  QT interval prolongation) was verified.
• 3. No significant differences in body temperature
  and arterial blood pressure were seen over the 24
  hour observation period after the ibutilide or
  d,l-sotalol injection. However, the QT and QTcF
  intervals prolongation were observed in both male
  and female conscious dogs.
• 4. The results demonstrated that the measurements
  of QT interval prolongation in canine model is a
  useful preclinical method to assess the effects
  of pharmaceuticals on the cardiac repolarization
  process. This pilot validation study confirmed
  UIC-TRLs ability to conduct telemetry
  measurements in conscious, freely moving animals.

Introduction The objective of this study was to
validate the telemetry system of acquisition and
analysis of the cardiovascular data. The
real-time evaluation data were collected from a
surgically implanted telemetry transmitter and
continuously monitored by the Data Sciences
International (DSI) DataquestARTTM data
acquisition program. The animal arterial blood
pressure (diastolic, systolic and mean blood
pressure), heart rate (HR), ECG measurements
including QT interval (with and without
correction for HR), body temperature and animal
activity were acquired. These data are usually
analyzed to investigate the potential undesirable
pharmacodynamic effects of the test compound on
physiological functions (Safety Pharmacology).
Delayed cardiac repolarization (QT interval
prolongation) may result in ventricular
arrhythmias, including a life-threatening
polymorphic ventricular tachycardia,
TdP. This information can be used as a
guide for accessing clinical benefits and risks,
and to identify particular aspects of adverse
effects which may warrant special monitoring or
precautionary measures during human clinical
trials.
Telemetry System

• References
• Gelzer AR, Ball HA. Validation of a telemetry
  system for measurement of blood pressure,
  electrocardiogram and locomotor activity in
  beagle dogs. Clin Exp Hypertens. 1997
  Oct19(7)1135-60.
• 2. Miyazaki H, Tagawa M. Rate-correction
  technique for QT interval in long-term telemetry
  ECG recording in beagle dogs. Exp Anim. 2002
  Oct51(5)465-75.

Figure 1 Data Sciences International (DSI)
canine telemetry system.