Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans.
BACKGROUND
The issue of drug-induced QT interval prolongation and torsades de pointes represents a major concern for pharmaceutical development. In this investigation, we examined the value of the isolated rabbit Purkinje fibre as an in vitro action potential (AP) assay to predict the potential of drugs to induce these undesirable adverse effects.


METHODS
First, we categorised the proarrhythmic risk of 26 medicinal products based on proportional reporting ratios for these two adverse events recorded in a US FDA database (Spontaneous Reporting System/Adverse Event Reporting System). Second, we measured drug effects on AP in rabbit Purkinje fibres. Finally, the results of the two analyses were compared to evaluate the predictive value of the in vitro assay.


RESULTS
Analysis of the clinical data classified the drugs into 14 positive, 7 negative and 5 questionable for proarrhythmic risk. Based on in vitro electrophysiological profiles, the drugs were grouped into four categories: (i) profile 1 drugs prolong repolarisation without slowing depolarisation; (ii) profile 2 drugs prolong repolarisation and also slow depolarisation; (iii) profile 3 drugs shorten repolarisation; and (iv) profile 4 drugs are without effects. All 14 clinical-positive drugs fell into profiles 1 or 2 (prolongers) with low safety margins (except probucol, which showed no effect, probably because of its low solubility). Clinical-negative drugs belonged mostly to profiles 3 or 4 (non-prolongers) [except clemastine and amlodipine, which were prolongers but had large safety margins]. Clinical-questionable drugs either did not prolong or prolonged slightly but produced additional electrophysiological effects opposing prolongation.


CONCLUSIONS
The rabbit Purkinje fibre is a valuable assay for evaluating the proarrhythmic liability of pharmaceuticals as it can reveal complex electrophysiological profiles that modulate repolarisation delay.
Aubert
Marion
M
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Osterwalder
Rolf
R
Wagner
Björn
B
Parrilla
Isabelle
I
Cavero
Icilio
I
Doessegger
Lucette
L
Ertel
Eric A
EA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D014150:Antipsychotic Agents / Q000009:adverse effects; D002317:Cardiovascular Agents / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000009:adverse effects; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced; D011237:Predictive Value of Tests; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012306:Risk; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D002317:Cardiovascular Agents; D006634:Histamine H1 Antagonists