Mark A. Osinski

Intravenous solid tip ECG lead placement in telemetry implanted dogs: Part 2: High quality telemetry signals yield high sensitivity to drug-induced changes.

INTRODUCTION Dogs are commonly used in cardiovascular drug safety assessment, and implanted telemetry models include subcutaneous or epicardial electrocardiogram (ECG) electrode placements. The purpose of this study was to determine the sensitivity of a canine telemetry model with intravenous ECG lead placement: the negative ECG lead (solid tip) inserted into the jugular vein and the positive lead sutured to the diaphragm. Reference drugs were administered to test the sensitivity to drug-induced changes. METHODS Twenty-four dogs were implanted with PCT or PCTP transmitters [Data Sciences International (DSI)]. Three reference drugs were administered: sotalol to eight PCT and milrinone to eight PCTP transmitter-implanted dogs. Twenty-four dogs received moxifloxacin (12 dogs/transmitter type). Telemetry data were collected for 25h and analyzed using double Latin squares for sotalol and milrinone data or a 4×4 or 3×6 parallel design for moxifloxacin data. Evaluated parameters were PR, QT, corrected QT (QTc), QRS, heart rate, left ventricular function, and hemodynamic data. Various correction factors for QTc interval were tested. Retrospective power analysis was performed to detect minimal absolute changes comparing a single to a double Latin square or the two parallel designs. RESULTS Expected changes on ECG and hemodynamic parameters were observed after administration of all reference drugs. The individual animal corrected QT (QTci) interval provided the optimal correction factor. Retrospective power analysis confirmed detection of smaller differences in double versus single Latin squares. Minimal detectable differences were smaller in both Latin squares compared to parallel designs, with smaller detectable differences in a 3×6 compared to a 4×4 parallel design. DISCUSSION The solid tip intravenous ECG lead configuration in dogs is a viable radiotelemetry model to detect drug-induced changes with high sensitivity. This model yields comparable signal quality and represents a refinement over epicardial ECG leads and allows for possible reduction in the number of animals if study design and size are selected based on needed assay sensitivity.

Intravenous solid tip lead placement in telemetry implanted dogs. Part 1: Surgical methods, signal quality, and pathological endpoints.

INTRODUCTION Electrocardiogram (ECG) signals in safety pharmacology studies are generally collected via subcutaneous or epicardial leads. Subcutaneous placement is an easier procedure, but signals often contain artifacts. Epicardial leads offer improved quality but require additional surgical expertise. Signal quality and tolerability of intravenous (IV)/diaphragmatic ECG leads were investigated as a less invasive alternative to the epicardial ECG lead approach for cardiovascular assessment in dogs. METHODS Twenty-eight beagle dogs were implanted with PCT (n=14) or PCTP (n=14) transmitters with IV (negative)/diaphragmatic (positive) ECG leads arranged in approximate Lead II configuration. Surgical time for previous epicardial and current IV lead placement approaches was compared. The ECG signals were assessed for up to 32 weeks post-surgery. Signal quality was assessed based on good wave/total wave (GW/TW) ratios calculated using ECG PRO (Ponemah Physiology Platform, Version 4.8) and variability in ECG parameter measurements for each surgical model. Clinical pathology was assessed on all animals before surgery and approximately 2 and 12 weeks post-surgery. A specialized necropsy was conducted on four animals (two PCT and two PCTP) to assess the tolerability of telemetry equipment; selected tissues were examined microscopically. RESULTS Surgical time using the IV lead method was approximately 18% shorter than the epicardial lead method. The GW/TW ratio for IV lead-implanted dogs indicated good durability of signal that was similar to epicardial leads. Intra- and inter-animal variability in ECG parameter measurements was similar between IV lead-implanted and epicardial lead-implanted dogs. Clinical pathology revealed no noteworthy findings, and the IV/diaphragmatic surgical approach had minimal consequences on local vasculature and associated implantation sites. DISCUSSION Advantages of the IV/diaphragmatic lead model include a less invasive and shorter surgical procedure; high tissue tolerance, ECG signal quality, and durability; and data processing procedures similar to that of epicardial leads. Therefore, the IV/diaphragmatic lead configuration is a viable alternative to more invasive surgical approaches for telemetry device implantation in dogs.

Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP).

INTRODUCTION Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics. METHODS Jacketed external telemetry with an implanted miniature blood pressure transmitter (JET-BP) was used to characterize the tolerability, functionality, and sensitivity of this study design in dogs. Thirty-six male or female beagles (n=6 dogs/sex/group) were administered vehicle control (reverse osmosis water) or etilefrine (1, 10mg/kg), sotalol (3, 30mg/kg), and hydralazine (1, 10mg/kg) on separate days. Telemetry data were evaluated for positive control article-related changes and retrospective power analysis was also completed. Animals were evaluated for instrumentation-related changes in clinical and anatomic pathology endpoints. RESULTS All three positive controls elicited the expected pharmacologic responses that were statistically different at high and low doses. Retrospective power analysis confirmed this study design was able to statistically differentiate minor (approximately 5 to 15%) changes in electrocardiography and blood pressure values. This study also demonstrated the potential advantages of combining cardiovascular data across sex when the test article exposure and pharmacodynamics were consistent. Data collection using miniature telemetry blood pressure transmitters did not result in anatomic or clinical pathology findings that would prevent their use in general toxicology studies. DISCUSSION This characterization study indicates that JET-BP in dogs offers a scientifically-robust method to evaluate novel therapeutics for potential cardiovascular liabilities.