QT Overestimation (False-Positives): How QTc Analysis Can Overestimate the Drug-Induced QT Prolongation

Drugs that affect the autonomic nervous system (e.g., produce change in heart rate, blood pressure, or change in autonomic state such as sleep) are more likely to cause a false-positive QTc finding because of significant limitations in the conventional methods of measuring QT prolongation in ECGs. This can be problematic when trying to distinguish the changes in QT interval brought on by drug induced delayed repolarization from changes that occur because of autonomic-mediated physiological responses. The QT interval is known to be dependent on both heart rate as well as history of heart rate. Therefore, to assess properly the effect on cardiac repolarization of a drug that affects the autonomic nervous system, several factors need to be taken into account. Changes in the RR interval and the history of the QT-RR relationships several minutes prior to the point of QT measurement must be noted. In addition, QT-RR dynamics under varying autonomic states also must be assessed.

The Fridericia correction factor (blue diagonal line) overestimates QT prolongation at high heart rates (striped area below 95% confidence bounds but above correction line). The over-correction by Fridericia leads to a probability of a false positive as a result of overestimated QTc prolongation.

Examples of Drugs Likely to Generate a False-Positive or False-Negative QTc Prolongation in a Conventional TQT Study

Two recent examples of drugs that do not affect hERG at their therapeutic concentrations but cause physiologically relevant vasodilatation and reflex tachycardia are vardenafil and alfuzosin. Both have been shown to produce QTc prolongation using standard correction factors. In general, any compound that reduces blood pressure leading to reflex tachycardia would be a candidate for a false-positive effect in a TQT study. Tachycardia as a result of direct cardiac stimulation, e.g., alpha vs. beta adrenergic agonists, may have varying degrees of arrhythmia liability and need to be assessed differently using both spatial and dynamic techniques. Likewise any compound causing increases in blood pressure can lead to false negative QTc results or under-estimation of pro-arrhythmia potential of the drug. One should also keep in mind that assessment of autonomic changes in normal subjects may be quite different than in the target patient population due to the disease/condition itself affecting the autonomic tone (sleep, psychosis, digestion, agitation etc).

Finally, any drug that is already known to block HERG that is still being pursued clinically should consider using both dynamic and spatial techniques because not all HERG blockers have equal cardiac liabilities (thioridazine vs. ziprasidone; moxifloxacin vs. sparfloxacin; fluoxetine vs. citalopram; telithromycin vs. erythromycin).

Case Studies: Drugs Terminated in Development Due to False-Positive/Overestimated QTc Prolongation

Compounds known to affect the autonomic nervous system, where the QTc measurements are problematic:

Vasodilators (Drugs that primarily induce reflex tachycardia):

o PDE5 inhibitors
o Ca channel blockers (some more than others since AV block may reduce reflex tachycardia)
o Alpha-blockers (hypotensives and drugs for benign prostatic hypertrophy, as well part of pharmacology like risperidone, ziprasidone)
o GABA agonists (drugs that induces sleep)
o CNS depressants (like chloral hydrate or alcohol)
o Drugs that induce histamine release acutely (many antibiotics given iv: quinolones, macrolides, polyamines)

Anticholinergics:

o M1 antagonist for urinary incontinence
o M5 antagonists for COPD
o Antipsychotics

Complex pharmacology (can increase or decrease autonomic tone):

o Serotonin reuptake inhibitors or modulators (depression and anxiety)
o Norepinephrine reuptake inhibitors (pain, incontinence, depression and anxiety)
o 5HT3 antagonists (antiemetics)
o D2 antagonists (antipsychotics, antiemetics)
o 5HT4 agonists (prokinetic agents)
o Antibiotics (quinolones, macrolides, novel?)
o Indirect effects (changes in nausea/emesis, thermoregulatory, etc.)
o Anything with sympathetic activity (decongestants, bronchodilators, beta-blockers)
o Analgesics (opioids more specifically but other novel mechanisms as well)
o Novel mechanisms where peptides are known to cause physiological changes (substance P, CRH, Kinases, proteases inhibitors)
o Cholinergics (dementia)

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VI Magnano AR, Holleran S, Ramakrishnan R, Reiffel JA and Bloomfield DM. Autonomic nervous system influences on QT interval in normal subjects. J Am Col Cardiol 39:1820-1826, 2002.

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