Abstract
Objective
The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) is known to elicit a negative chronotropic effect at treatment initiation that attenuates over time with continued dosing. The authors determined the effect of combining a single dose of fingolimod with steady-state atenolol or diltiazem on heart rate and mean arterial pressure.
Methods
In a partially randomized, single-blind, placebo-controlled, three-period, crossover study, 25 healthy subjects received (1) a single oral 5-mg dose of fingolimod, (2) either 50 mg atenolol or 240 mg diltiazem once daily for 5 days, and (3) the antihypertensive for 5 days and a single dose of fingolimod on day 5. Telemetry and pharmacokinetic data were collected.
Results
The daytime mean heart rate nadir was 15% lower when fingolimod was combined with atenolol (42 ± 7 bpm) compared with fingolimod alone (51 ± 9 bpm) yielding a combination/monotherapy ratio of 0.85 (90%CI, 0.79–0.92). The daytime mean heart rate nadir from fingolimod alone (55 ± 5 bpm) was not altered when combined with diltiazem (56 ± 8 bpm) yielding a ratio of 0.99 (0.94–1.05). There was no clinically relevant change in mean arterial pressure when fingolimod was administered with atenolol or diltiazem compared with administration of the drugs alone in normotensive subjects. The pharmacokinetics of the drugs were not altered during coadministration.
Conclusion
Adding fingolimod to a beta-blocker such as atenolol resulted in a moderately lower mean heart rate nadir compared with fingolimod alone. However, subjects who had a stronger negative chronotropic response to fingolimod alone (nadir < 50 bpm) had minimal or no further reduction in heart rate with the drug combination. Adding fingolimod to a calcium channel blocker such as diltiazem did not further lower the heart rate compared to fingolimod alone.
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References
Brinkmann V, Lynch KR (2002) FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Current Opin Immunol 14:569–575
Kappos L, Antel J, Comi G et al (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124–1140
Kovarik JM, Schmouder RL, Slade AJ (2004) Overview of FTY720 clinical pharmacokinetics and pharmacology. Ther Drug Monit 26:585–587
Tedesco-Silva H, Pescovitz MD, Cibrik D et al (2006) Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 82:1689–1697
Koyrakh L, Lujan R, Colon J et al (2005) Molecular and cellular diversity of neuronal G-protein-gated potassium channels. J Neurosci 25:11468–11478
Schmouder RL, Barilla D, Wang Y et al (2006) FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol 46:895–904
Kovarik JM, Schmouder RL, Barilla D et al (2004) Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol 57:586–591
Heel RC, Brogden RN, Speight TM et al (1979) Atenolol: a review of its pharmacological properties and therapeutic efficacy in angina pectoris and hypertension. Drugs 17:425–460
McAuley BJ, Schroeder JS (1982) The use of diltiazem hydrochloride in cardiovascular disorders. Pharmacotherapy 2:121–133
Acknowledgements
This study was sponsored by Novartis Pharmaceuticals. Several of the authors are employees of Novartis as identified in the affiliations.
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Kovarik, J.M., Lu, M., Riviere, GJ. et al. The effect on heart rate of combining single-dose fingolimod with steady-state atenolol or diltiazem in healthy subjects. Eur J Clin Pharmacol 64, 457–463 (2008). https://doi.org/10.1007/s00228-007-0448-4
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DOI: https://doi.org/10.1007/s00228-007-0448-4