Detecting drug-induced prolongation of the QRS complex: new insights for cardiac safety assessment.
BACKGROUND
Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I(Na)) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I(Na), this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation.


METHODS
Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1h period from 1h pre-dose to 5h post-dose.


RESULTS
Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E(max) 13% and 20% respectively, P<0.01-0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of +0.7 ± 0.5 ms (quinidine, NS), +1.8 ± 0.8 ms (mexiletine, P<0.05) and +2.8 ± 0.8 ms (flecainide, P<0.01) (calculated as QRS at basal HR-QRS at high HR).


CONCLUSIONS
Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function.
Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, UK. caroline.cros@hotmail.co.uk
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Cros
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Skinner
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Moors
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Lainee
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Valentin
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D005424:Flecainide / Q000494:pharmacology / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008801:Mexiletine / Q000494:pharmacology* / Q000633:toxicity; D018408:Patch-Clamp Techniques; D011802:Quinidine / Q000494:pharmacology* / Q000633:toxicity; D013686:Telemetry; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity
D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine; D011802:Quinidine; D005424:Flecainide