A cardiovascular monitoring system used in conscious cynomolgus monkeys for regulatory safety pharmacology. Part 2: Pharmacological validation.
BACKGROUND
This project addresses the validation study design of a test system using a telemetered non-human primate model for cardiovascular safety pharmacology evaluation.


METHODS
In addition to non-pharmacological validation including installation and operation qualifications, performance qualification (locomotor activity and cardiovascular evaluations) was completed on free-moving cynomolgus monkeys by quantifying the degree of cardiovascular response measured by the telemetric device to various positive control drugs following their intravenous administration. Remifentanil (0.0005, 0.001, 0.002, 0.004, 0.008 and 0.016 mg/kg) was given to induce bradycardia and hypotension. Medetomidine (0.04 mg/kg) was used to induce an initial phase of hypertension followed by hypotension and bradycardia. Esmolol (0.5, 1.0 and 2.0 mg/kg) was used to induce bradycardia. Dopamine (0.002, 0.008, 0.01, 0.02, 0.03 and 0.05 mg/kg/min) was infused over 30 min to induce an increase in arterial and pulse pressures and tachycardia. Amiodarone (0.4, 0.8 and 1.6 mg/kg/min) was infused over 10 min to induce QT interval prolongation. Potassium chloride (0.08 mEq/kg/min) was infused for periods of less than 30 min to induce electrocardiographic (EKG) changes characteristic of hyperkalemia. Reliability was evaluated over 60 days.


RESULTS
Monitoring with a reference methodology and the telemetry system was important in order to evaluate precision and accuracy of the test system. Positive control drugs produced a wide range of cardiovascular effects with different amplitudes, which were useful in identification of the limits of the test system.


CONCLUSIONS
Reference monitoring methods and selection of a battery of positive control drugs are important to ensure proper test system validation. Drugs inducing not only QT prolongation but also positive and negative chronotropic effects, positive and negative systemic arterial pressure changes and ECG morphology alterations were useful to identify test system limitations during performance qualification. ECG data processing at significantly elevated heart rates revealed that a trained observer should review all cardiac cycles evaluated by computer.
Authier
Simon
S
LAB Research Inc., 445 Armand Frappier, Laval, Quebec, Canada. authiers@labresearch.com
Tanguay
Jean-Francois
JF
Gauvin
Dominique
D
Fruscia
Rocky Di
RD
Troncy
Eric
E
D058647:Adrenergic alpha-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000633:toxicity; D000638:Amiodarone / Q000008:administration & dosage / Q000633:toxicity; D000701:Analgesics, Opioid / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology*; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016903:Drug Monitoring / Q000295:instrumentation / Q000379:methods*; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008252:Macaca fascicularis / Q000502:physiology*; D020926:Medetomidine / Q000008:administration & dosage / Q000633:toxicity; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity; D011412:Propanolamines / Q000008:administration & dosage / Q000633:toxicity; D000077208:Remifentanil; D015203:Reproducibility of Results; D012849:Sinoatrial Node / Q000187:drug effects / Q000503:physiopathology; D013686:Telemetry / Q000295:instrumentation / Q000379:methods
D058647:Adrenergic alpha-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D000701:Analgesics, Opioid; D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011412:Propanolamines; C036604:esmolol; D020926:Medetomidine; D000638:Amiodarone; D000077208:Remifentanil