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

• Published in: British journal of clinical pharmacology 2008-08, Vol.66 (2), p.199-206
• Main Authors: Kovarik, John M., Slade, Alan, Riviere, Gilles‐Jacques, Neddermann, Daniel, Maton, Steve, Hunt, Thomas L., Schmouder, Robert L.
• Format: Article
• Language: English
• Subjects: Adult; Anti-Arrhythmia Agents - administration & dosage; Anti-Arrhythmia Agents - pharmacology; Area Under Curve; atropine; Atropine - administration & dosage; Atropine - pharmacology; Biological and medical sciences; bradycardia; Cardiac dysrhythmias; Cardiology. Vascular system; Circadian Rhythm - drug effects; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Interactions; Female; fingolimod; Fingolimod Hydrochloride; Heart; heart rate; Heart Rate - drug effects; Humans; Immunosuppressive Agents - adverse effects; Infusions, Intravenous; Male; Medical sciences; Middle Aged; Pharmacodynamics; Pharmacology. Drug treatments; Propylene Glycols - adverse effects; Sphingosine - adverse effects; Sphingosine - analogs & derivatives; Telemetry - methods; Time Factors; Treatment Outcome
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2008.03199.x

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. AIMS The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod. METHODS In 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. RESULTS Fingolimod administration alone yielded a heart rate nadir of 51 ± 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 ± 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 ± 9 beats min−1 (placebo) to 64 ± 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. CONCLUSIONS Atropine 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.