Detection of QTc interval prolongation using jacket telemetry in conscious non‐human primates: comparison with implanted telemetry. (January 2014)

• Record Type: Journal Article
• Authors: Derakhchan, K; Chui, R W; Stevens, D; Gu, W; Vargas, H M
• Is Part Of: British journal of pharmacology. Volume 171:Number 2(2014:Jan.)
• Page Start: 509
• Page End: 522
• Publication Date: 2014-01
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12484
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12484-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>During repeat‐dose toxicity studies, ECGs are collected from chemically or physically‐restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non‐invasive jacket‐based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non‐human primates (NHPs), previously implanted with a PCT transmitter.</p> </sec> <sec id="bph12484-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg<sup>−1</sup>) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.</p> </sec> <sec id="bph12484-sec-0003" sec-type="section"> <title>Key Results</title> <p>Sotalol attained C<sub>max</sub> values 1–3 hours after dosing, and exhibited dose‐proportional exposure. In jacketed NHPs, sotalol dose‐dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg<sup>−1</sup> sotalol, respectively, compared with time‐matched vehicle‐treated animals. Overall, JET‐derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.</p> </sec> <sec id="bph12484-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint‐based ECG because high‐density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.</p> </sec> </abstract>