Practical Application of Guinea Pig Telemetry System for Qt Evaluation

Abstract

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Computerized electrocardiography in healthy conscious guinea pigs (Cavia porcellus)

“…Guinea-pigs are a model for electrophysiological and pharmacological investigations (Farraj et al 2011). In vivo guinea-pig models were studied over the years, both with conscious (Shiotani et al 2005) and anesthetized animals (Morissette et al 2013). This model is especially used to evaluate new drugs before they are allowed for commercialization, particularly those with high risk of arrhythmias and/or alterations of QT interval (Tárraga et al 2000).…”

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

“…However, as compared to the anesthetized guinea-pig model, there are relatively few reports on cardiovascular effects of drugs obtained from conscious guinea-pigs, particularly from studies using telemetry. This lack of in vivo data can be explained at least partly by the difficulties to achieve proper anesthesia/surgery and appropriate placement of ABP catheters in guinea-pigs as compared to other species [98][99][100][101]. Some teams use restrained conscious guinea-pigs, maintained quiet in slings, to assess the proarrhythmic liabilities of drugs.…”

“…Some pharmaceutical laboratories have already adopted the telemetered conscious guinea-pig in their screening strategies as a valuable tool for assessing the arrhythmogenic potential of new drug candidates in the early stage of drug development. This model has been shown as suitable to detect QTc prolongation induced by various therapeutic classes-related compounds including antiarrhythmic agents (quinidine, sotalol, dofetilide, bepridil), antihistaminics (terfenadine), prokinetics (cisapride), or psychiatric drugs (haloperidol, pimozide, thiodazine), along with possible T wave shape modifications, or the absence of any QTc changes with negative controls [100,101]. Importantly, whatever the guinea-pig model used, i.e., anesthetized versus conscious, the choice of appropriate methods for correcting QT interval versus heart rate is crucial to correctly evaluate QTc changes.…”

Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs

“…Although QT prolongation and/or torsades de pointes caused by coadministration of terfenadine and ketoconazole has been studied in animals and humans [16,17], most of the studies were done in anesthetized animals [1,4,5]. With the use of a telemetry system, experimentation can be performed on conscious unstressed animals [7,13,[19][20][21]. Few studies have reported the ef-fects of drug-induced QT interval prolongation in conscious guinea pigs using a telemetry system [7,21].…”

“…With the use of a telemetry system, experimentation can be performed on conscious unstressed animals [7,13,[19][20][21]. Few studies have reported the ef-fects of drug-induced QT interval prolongation in conscious guinea pigs using a telemetry system [7,21]. Among them, a high dose of ketoconazole (400 mg/kg, po) administered to guinea pigs induced a significant prolongation of the QTc interval [7].…”