Any compound causing increases in blood pressure can lead to false negative or under-estimated QTc results and therefore an under-estimation of pro-arrhythmia potential of the drug. For example, cisapride (Prepulsid™), a drug for gastro-intestinal disorders, was associated with numerous arrhythmic events, including 341 cases of life-threatening cardiac arrhythmias and 15 sudden-cardiac arrests over a period of six years on the market . By conventional methods of QT measurement (QTc) cisapride alone shows relatively small dose-related prolongation in humans at therapeutic concentrations starting at approximately 2 nM free drug, causing a 6 ms increase in QTc . This is well below the 10 ms threshold of regulatory concern according to the current ICH E14 guidance. However, cisapride causes excessive QT prolongation that may lead to life-threatening arrhythmias when taken with substances which inhibit cytochrome P450 3A4, with other agents which prolong the QT-interval, in patients with predisposing factors for arrhythmia or pre-existing QT-prolongation and in patients with hepatic failure. Many patients were taking interacting medicines, most commonly erythromycin, fluconazole, clarithromycin and amiodarone.

The Fridericia correction factor (blue diagonal line) underestimates QT prolongation at slow heart rates (shaded area above 95% confidence bounds but below correction line).The under-correction by Fridericia leads to a lower, but still significant probability of a false-negative o underestimated QTc prolongation finding for drugs that increase the blood pressure and induce reflex bradycardia.

However, more sophisticated analyses, such as QTbtb can produce a more accurate estimation of the cardiac risk for drugs such as cisapride. Examination of the beat-to-beat plots of the QT versus RR interval relationship in dogs revealed that the upward shift and generation of aberrant outliers seems to predominate at higher heart rates or shorter RR intervals on cisapride (Fig. 2). It can be speculated that these aberrant outliers may be indicative of the inherent susceptibility toward arrhythmogenesis and are usually not detected by more traditional averaging of the data in QTc analysis.

Click to view Cisapride Infusion

Cisapride infusion in a conscious dog: The QT-RR interval relationship on a beat-to-beat basis in an individual dog treated with cisapride by intravenous infusion. Cisapride at a plasma free drug concentration of 144 nM caused an upward shift and increase in the number of aberrant outliers at all RR intervals represented by the red points on the plot.

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1 Fossa AA, Wisialowski T, Magnano A, Wolfgang E, Winslow R, Gorczyca W, Crimin K, and Raunig DL. Dynamic beat-to-beat model of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition. J Pharmacol Exp Ther 312:1 – 11, 2005.

2 Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol 2001 June;96(6):1698-703.

3 van Haarst AD, van’t Klooster GAE, van Gerven JMA, Schoemaker RC, van Oene JC, Burggraaf J, Coene M-C, and Cohen AF (1998) The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 64:542–546.  

4 Fossa AA et al. The Relationship of Clinical QT Prolongation to Outcome in the Conscious Dog Using a Beat-to-Beat QT-RR Interval Assessment. JPET 202:828–833, 2002.

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