469 Fingolimod (Gilenya®), a New Oral Treatment for Relapsing Forms of Multiple Sclerosis, Causes Bradycardia and Prolongs the QTC Interval

Abstract

Fingolimod hydrochloride (Gilenya®) is a new oral agent that was approved on March 9 2011 by Health Canada for treating relapsing forms of Multiple Sclerosis (MS) in adults. Fingolimod is used to reduce the frequency of flare-ups (clinical exacerbations) and delay physical disability. It is a sphingosine 1-phosphate receptor modulator that reduces the migration of autoagressive lymphocytes into the CNS. Interestingly, as of February 27 2012, eleven fingolimod-associated sudden deaths have been reported internationally. Four of these 11 reports involved serious heart-related events including one severe cardiac arrhythmia. A patient in the United States died within 24 hours of taking its first dose. Of note, as specified in the product labelling, QTc interval prolongation has been reported during clinical studies with fingolimod. Our aim was to evaluate the effects of fingolimod on cardiac electrophysiology. 1) Ex vivo Langendorff retroperfusion experiments: Isolated hearts from male Hartley guinea pigs (n=4) were either let at their natural sinus rhythm (SR) or paced at basic cycle lengths (BCL) of 250 or 200 ms. They were allowed to stabilize and were then exposed for 15 minutes to fingolimod 10 or 100 nmol/L to assess drug-induced effect on monophasic action potential duration measured at 90% repolarization (MAPD90). 2) In vivo wireless cardiac telemetry experiments: Guinea pigs (n=4) implanted with radio transmitters were administered a single oral gavage dose of fingolimod 0.0625 mg/kg and 24h ECG recordings were made. See table.Tabled 1 Previous clinical studies have shown steady-state plasma concentrations of fingolimod of ≈11 nmol/L at a standard dose of 0.5 mg/day. In the present study, fingolimod had no significant ex vivo effect on MAPD90 at clinically relevant concentrations (10-100 nmol/L). However, in vivo, the drug caused significant prolongations of the RR, QT and QTc intervals. A trend towards PR prolongation was also observed. Interestingly, reversible AV blocks were observed in 4/4 of the animals after a single oral administration of fingolimod. When used at recommended dose, fingolimod may therefore increase the risk for severe arrhythmias, including life-threatening torsades de pointes, thus explaining cases of cardiac sudden deaths.