title: The effect on heart rate of combining single-dose fingolimod with steady-state atenolol or diltiazem in healthy subjects.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Novartis Pharma, Building WSJ 210.423, 4002, Basel, Switzerland. john.kovarik@novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Michael
authors.initials: M
authors.lastname: Lu
authors.forename: Gilles-Jacques
authors.initials: GJ
authors.lastname: Riviere
authors.forename: Irene
authors.initials: I
authors.lastname: Barbet
authors.forename: Steve
authors.initials: S
authors.lastname: Maton
authors.forename: D Ronald
authors.initials: DR
authors.lastname: Goldwater
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schmouder
mesh_terms: D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001262:Atenolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory; D018592:Cross-Over Studies; D004110:Diltiazem / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D000068876:Fingolimod Hydrochloride; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D016037:Single-Blind Method; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D001262:Atenolol; D004110:Diltiazem; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine