The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects

Abstract

WHAT IS KNOWN ABOUT THIS SUBJECT• Clinical pharmacology and clinical therapeutic studies of fingolimod demonstrate that heart rate after the initial dose decreases by about 10-20% while normal circadian rhythm is preserved. With continued daily dosing, heart rate returns to normal over the next 2 weeks. • This negative chronotropic effect is consistent with the binding of fingolimod-phosphate to the sphingosine-1-phosphate receptor on atrial myocytes. WHAT THIS STUDY ADDS• The present clinical pharmacology study demonstrates that atropine administered at usual therapeutic doses can prevent the decrease in heart rate when given concomitantly with fingolimod and can counteract the decrease in heart rate when give at the time of the typical heart rate nadir, 4 h after the fingolimod dose.• Although therapeutic intervention is rarely needed for reduced heart rate in patients receiving fingolimod, atropine is an option, should this be desired. AIMSThe authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod. METHODSIn this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110-120 beats min -1 ) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose. Continuous telemetry measurements were made for 24 h after each fingolimod dose. RESULTSFingolimod administration alone yielded a heart rate nadir of 51 Ϯ 5 beats min -1 at a median 4 h postdose with heart rate remaining depressed at 51-64 beats min -1 over the rest of the day. Concurrent administration of fingolimod and atropine yielded a nadir of 66 Ϯ 6 beats min -1 resulting in an atropine : placebo ratio (90% confidence interval) of 1.30 (1.22, 1.36). When atropine was administered at the time of the nadir, it was able to reverse the negative chronotropic effect of fingolimod from a heart rate of 56 Ϯ 9 beats min -1 (placebo) to 64 Ϯ 8 beats min -1 (atropine) resulting in an atropine : placebo ratio of 1.15 (1.04, 1.26). Atropine had no influence on the pharmacokinetics of fingolimod. CONCLUSIONSAtropine administered concurrently with fingolimod prevented the heart rate nadir that typically occurs 4 h postdose. Atropine administered at the time of the heart rate nadir was able to reverse the negative chronotropic effect of fingolimod.

Elimination of a Hydroxyl Group in FTY720 Dramatically Improves the Phosphorylation Rate

“…3B). Results with human patients indicate that the equilibrium between FTY720 and its phosphate rests more heavily in favor of dephosphorylation: the plasma concentration of FTY-P drops below that of FTY720 12 to 24 h after a single 5-mg dose of FTY720; thereafter, FTY-P declines as a proportion of the FTY720 concentration (Kovarik et al, 2008(Kovarik et al, , 2009. On this basis, one would predict that AAL(R) would achieve effective immunosuppression at a significantly lower dose in humans than FTY720.…”

Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction

“…S1P 1 has been shown to regulate sinus bradycardia, is coupled to G protein-coupled inwardly-rectifying potassium (Guo et al, 1999), and is responsible for the atropine sensitive vagal sinus bradycardia (Kovarik et al, 2008;Fryer et al, 2012;Legangneux et al, 2013). S1P 3 in mice has rich expression at the mRNA level on cells of neural crest origin (Meng and Lee, 2009) and was recently shown to be transcriptionally present along S1pr1 and S1pr2 transcripts in the AVN of rats.…”

“…FTY720 treatment has additionally revealed an increased incidence of atrioventricular (AV) disturbances during the first dose, including AV block and asystole, particularly in subgroups of patients with preexisting cardiac conditions that require other therapeutics, i.e., beta blockers and calcium channel blockers, to maintain adequate cardiovascular dynamics (Vanoli et al, 2014). Atropine reversal of the sinus bradycardia (Kovarik et al, 2008) and the demonstration of sinus bradycardia with S1P 1/5 -selective agonists in humans (Legangneux et al, 2013) as well as rodents (Fryer et al, 2012) suggest that sinoatrial node (SAN) effects and those events resulting from alterations in AV-nodal conduction might be distinctly regulated.…”

Advances in the treatment of relapsing–remitting multiple sclerosis – critical appraisal of fingolimod

“…There were no episodes of symptomatic bradycardia occurring beyond 24 hours, and no clinically significant effect on heart rate was observed with sustained administration of the drug 46,47. Although during clinical trials, pharmacological treatment has never been required to treat bradycardia, it has been suggested that intravenous atropine can ameliorate the negative effect of fingolimod on cardiac rhythm 49. In addition to transient changes in cardiac rhythm, fingolimod induced cardiac conduction abnormalities, including first- and second-degree atrioventricular block.…”