Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys.
OBJECTIVE
The non-selective beta-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 abstract 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.


METHODS
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.


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
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.
Lynch
J J
JJ
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA. james.j.lynch@abbott.com
Wilson
A W
AW
Hernandez
L E
LE
Nelson
R A
RA
Marsh
K C
KC
Cox
B F
BF
Mittelstadt
S W
SW
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D013015:Sotalol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013045:Species Specificity; D013686:Telemetry / Q000379:methods
D000319:Adrenergic beta-Antagonists; D013015:Sotalol