Calculation of QT shift in non clinical safety pharmacology studies.
BACKGROUND
Drug-induced QT interval prolongation is a major concern in new drug candidate development. This study presents a method of assessment of drug-induced QT interval prolongation without need for QT correction in conscious Beagle dogs and Cynomolgus monkeys monitored by telemetry. Accuracy and reliability are analysed by comparison with a reference QT correction method (Holzgrefe) from experiments performed with reference substances terfenadine, thioridazine and sotalol.


METHODS
The QT shift method principle is assessment of any drug-induced QT interval shift directly from the individual QT/RR relationship. The individual QT/RR relationship is built from a treatment-free 24-hour recording period. QT and RR intervals are determined from a beat-to-beat analysis. A probabilistic method is used to define the individual QT/RR relationships. Checks were performed to compare results obtained with the QT shift method and the QT correction methods. The robustness of the QT shift method was tested under various conditions of drug-induced heart rate change (i.e. normal, bradycardia and tachycardia).


RESULTS
The extent of agreement with the used reference QT correction method, Holzgrefe formula, was excellent (3-4 ms) in both animal species under the various drug induced effects on heart rate. The statistical sensitivity threshold for detection of QT prolongation according to a standard safety pharmacology study design was 7-8 ms.


CONCLUSIONS
When combined with the probabilistic determination of individual QT/RR relationships, this simple method provides a direct assessment of a drug-induced effect on QT interval, without any curve fitting or application of correction formula. Despite noticeably different shapes in QT/RR relationships, the QT shift method is applicable to both Beagle dogs and Cynomolgus monkeys. It is likely that the QT shift method will be particularly helpful in problematic cases, enabling detection of drug-induced prolongation of less than 10 ms.
Champeroux
Pascal
P
Centre de Recherches Biologiques, CERB, Chemin de Montifault, 18800 Baugy, France. pascal.champeroux@cerb.fr
Martel
Eric
E
Fowler
John Sinclair Lawrence
JS
Maurin
Anne
A
Sola
Marie Laure
ML
Jude
Sébastien
S
Elamrani
Francine
F
Weyn
Andrée Anne
AA
Laveissiere
Arnaud
A
Lala
Patricia
P
Richard
Serge
S
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology; D004285:Dogs; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography / Q000187:drug effects / Q000295:instrumentation* / Q000592:standards*; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000009:adverse effects / Q000494:pharmacology; D008133:Long QT Syndrome / Q000139:chemically induced*; D008252:Macaca fascicularis; D008297:Male; D015233:Models, Statistical; D010627:Phenethylamines / Q000009:adverse effects / Q000494:pharmacology; D012015:Reference Standards; D012680:Sensitivity and Specificity; D013015:Sotalol / Q000009:adverse effects / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D013686:Telemetry; D016593:Terfenadine / Q000009:adverse effects / Q000494:pharmacology; D013881:Thioridazine / Q000009:adverse effects / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D018492:Dopamine Antagonists; D039563:Histamine H1 Antagonists, Non-Sedating; D010627:Phenethylamines; D013449:Sulfonamides; D016593:Terfenadine; D013015:Sotalol; D013881:Thioridazine; C063533:dofetilide