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

Abstract

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.

Figure 1

Mean heart rate trajectories after oral placebo (○), fingolimod (▵), and fingolimod with concurrent atropine (▪). Concurrent atropine is able to prevent the absolute nadir heart rate observed for fingolimod alone. The vertical dashed line identifies the end of the intravenous titration phase

Figure 2

Mean heart rate trajectories after oral placebo (○), fingolimod (▵), and fingolimod with delayed atropine (▪). Atropine is able to reverse the heart rate nadir observed for fingolimod alone. The vertical dashed lines identifies the intravenous titration phase

Figure 3

Mean fingolimod and fingolimod-phosphate concentration profiles after concurrent administration of fingolimod with intravenous atropine or placebo. Bars are from the 95% confidence intervals. Fingolimod + IV atropine, (•); fingolimod + IV placebo, (▪); fingolimod-phosphate + IV atropine, (○); fingolimod-phosphate + IV placebo, (□)