Dose–response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys

• Published in: British journal of pharmacology Vol. 154; no. 7; pp. 1439 - 1445
• Main Authors: Lynch, J J, Wilson, A W, Hernandez, L E, Nelson, R A, Marsh, K C, Cox, B F, Mittelstadt, S W
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2008; Nature Publishing; Nature Publishing Group
• Subjects: Administration, Oral; Adrenergic beta-Antagonists - administration & dosage; Adrenergic beta-Antagonists - pharmacokinetics; Adrenergic beta-Antagonists - toxicity; Animals; arterial blood pressure; Biological and medical sciences; Blood Pressure - drug effects; body temperature; Body Temperature - drug effects; Cardiac dysrhythmias; Cardiology. Vascular system; cardiovascular; Cynomolgus; Dose-Response Relationship, Drug; electrocardiogram; Electrocardiography; Heart; heart rate; Heart Rate - drug effects; Macaca fascicularis; Male; Medical sciences; Models, Animal; monkey; Pharmacology. Drug treatments; Primates; QT prolongation; Research Papers; safety pharmacology; sotalol; Sotalol - administration & dosage; Sotalol - pharmacokinetics; Sotalol - toxicity; Species Specificity; telemetry; Telemetry - methods; Arrhythmia; Toxicity; Monkey; Cardiovascular disease; β-Adrenergic receptor; Dose activity relation; electrocardiogram; arterial blood pressure; Heart block; Heart disease; Primates; Electrocardiography; Arterial pressure; safety pharmacology; Antagonist; Safety; Sotalol; Body temperature; Prolonged QT interval; Antiarrhythmic agent; cardiovascular; Conduction disorder; Heart rate; Vertebrata; Mammalia; QT prolongation; Sulfonamides; Animal; telemetry; Hemodynamics; Circulatory system; Beta blocking agent
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.206

Background and purpose: The non‐selective β‐adrenoceptor antagonist, D,L‐sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in form, regarding the dose–response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose– and plasma–response effects of orally administered sotalol on cardiovascular function in conscious non‐human primates. Experimental approach: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg−1 of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. Key results: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. Conclusions and implications: The current study helps demonstrate the validity of utilizing telemetry‐instrumented non‐human primates for the cardiovascular safety pharmacology assessment of drugs prior to first‐in‐human testing, and its findings may serve as a reference source for the dose– and plasma–response effects of orally administered sotalol in conscious monkeys. British Journal of Pharmacology (2008) 154, 1439–1445; doi:10.1038/bjp.2008.206; published online 2 June 2008