QT interval correction for drug-induced changes in body temperature during integrated cardiovascular safety assessment in regulatory toxicology studies in dogs: A case study.
BACKGROUND
Cardiovascular safety assessment requires accurate evaluation of QT interval, which depends on the length of the cardiac cycle and also on core body temperature (BT). Increases in QT interval duration have been shown to be associated with decreases in BT in dogs.


METHODS
An example of altered QT interval duration associated with changes in body temperature observed during a 4-week regulatory toxicology study in dogs is presented. Four groups of Beagle dogs received the vehicle or test item once on Day 1, followed by a 4-week observation period. Electrocardiogram (ECG) parameters were continuously recorded on Days 1 and 26 by jacketed external telemetry (JET). Core body temperature (BT) was measured with a conventional rectal thermometer at appropriate time-points during the Day 1 recording period.


RESULTS
Decreased BT was observed approximately 2h after treatment on Day 1, along with increased QT interval duration corrected according to the Van de Water formula (QTcV), but the effect was no longer observed after correction for changes in BT [QTcVcT=QTcV-14(37.5-BT)] according to the Van der Linde formula. No significant changes in QTcV were reported at the end of the observation period, on Day 26.


CONCLUSIONS
The present study demonstrates that core body (rectal) temperature can easily be monitored at appropriate time-points during JET recording in regulatory toxicology studies in dogs, in order to correct QT interval duration values for treatment-related changes in BT. The successful application of the Van der Linde formula to correct QTc prolongation for changes in BT was demonstrated.
CiToxLAB France, B.P. 563, Evreux, France.
Abdel-Ilah
AI
El Amrani
CiToxLAB France, B.P. 563, Evreux, France.
Francine
F
El Amrani-Callens
CiToxLAB France, B.P. 563, Evreux, France.
Stéphane
S
Loriot
CiToxLAB France, B.P. 563, Evreux, France.
Pramila
P
Singh
CiToxLAB France, B.P. 563, Evreux, France. Electronic address: roy.forster@fr.citoxlab.com.
Roy
R
Forster
D000465:Algorithms; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D012449:Safety; D013686:Telemetry; D014116:Toxicology / Q000331:legislation & jurisprudence / Q000379:methods*
D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers
Core body temperature; Dog; Electrocardiogram; Jacketed external telemetry; QT interval