A Mechanistic Study to Assess Whether Isoproterenol Can Reverse the Negative Chronotropic Effect of Fingolimod

¹ Novartis Pharmaceuticals
² PPD Development Clinics

^* To whom correspondence should be addressed. E-mail: john.kovarik{at}pharma.novartis.com.

	Abstract

The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) elicits a negative chronotropic effect at treatment initiation that attenuates thereafter. The authors determined whether isoproterenol can counteract this effect. In this randomized, crossover study, 14 healthy subjects received 5 infusions of isoproterenol (titrated to increase heart rate to 100-120 bpm) or intravenous placebo. The first infusion was 2 hours before and the other 4 infusions were between 3 and 6 hours after a 5-mg oral dose of fingolimod. Telemetry and pharmacokinetic data were collected for 24 hours. During isoproterenol infusion 1 (before fingolimod administration), heart rate was increased 80% from preinfusion 68 ± 9 bpm to a maximum 122 ± 15 bpm. Administration of fingolimod decreased heart rate from 73 ± 11 bpm predose to a nadir of 57 ± 8 bpm. The subsequent isoproterenol infusion 2 in the presence of fingolimod increased mean heart rate by 85% to a maximum 105 ± 21 bpm. A 41% higher total isoproterenol dose was needed to increase heart rate to the target range with fingolimod (97 ± 6 mcg) compared with isoproterenol alone (69 ± 27 mcg). Isoproterenol infusions 3 to 5 had similar effects on heart rate as infusion 2. Fingolimod had no significant influence on blood pressure responses to isoproterenol. Isoproterenol did not alter the pharmacokinetics of fingolimod. The pure beta-agonist isoproterenol can reverse the heart rate reduction that occurs transiently after initiating fingolimod treatment.