VALIDATION OF SAFETY PHARMACOLOGY ASSESSMENT OF CARDIOVASCULAR FUNCTION IN CONSCIOUS DOGS WITH TWO POSITIVE CONTROLS (SOTALOL AND IBUTILIDE) Chen, Ya-Fei; Lindeblad, Matthew; Lyubimov, Alexander Toxicology Research Laboratory, University of Illinois at Chicago, 1940 W. Taylor St, Chicago, IL 60612: VALIDATION OF SAFETY PHARMACOLOGY ASSESSMENT OF CARDIOVASCULAR FUNCTION IN CONSCIOUS DOGS WITH TWO POSITIVE CONTROLS (SOTALOL AND IBUTILIDE) Chen, Ya-Fei; Lindeblad, Matthew; Lyubimov, Alexander Toxicology 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.
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-TRL’s 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.
Results
Telemetry System
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.
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 Oct;19(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 Oct;51(5):465-75. Figure 1: Data Sciences International (DSI) canine telemetry system. Figure 2: Example of data (MAP, HR, Temp and ECG) recorded by DSI DATAQUEST ART system.