The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects.
OBJECTIVE
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.
Kovarik
John M
JM
Novartis Pharmaceuticals, Exploratory Development, Basel, Switzerland. john.kovarik@novartis.com
Slade
Alan
A
Riviere
Gilles-Jacques
GJ
Neddermann
Daniel
D
Maton
Steve
S
Hunt
Thomas L
TL
Schmouder
Robert L
RL
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D000068876:Fingolimod Hydrochloride; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011409:Propylene Glycols / Q000009:adverse effects*; D013110:Sphingosine / Q000009:adverse effects / Q000031:analogs & derivatives*; D013686:Telemetry / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome
D000889:Anti-Arrhythmia Agents; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D001285:Atropine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine