Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects

Br J Clin Pharmacol. 2013 Mar;75(3):831-41. doi: 10.1111/j.1365-2125.2012.04400.x.


Aim: Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects.

Methods: Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed.

Results: Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non-titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non-titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min⁻¹; P ≤ 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo.

Conclusion: Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Azetidines / administration & dosage*
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology
  • Benzyl Compounds / administration & dosage*
  • Benzyl Compounds / pharmacokinetics
  • Benzyl Compounds / pharmacology
  • Bradycardia / prevention & control
  • Dose-Response Relationship, Drug
  • Female
  • Heart Rate / drug effects*
  • Humans
  • Male
  • Middle Aged
  • Receptors, Lysosphingolipid / metabolism*
  • Young Adult


  • Azetidines
  • Benzyl Compounds
  • Receptors, Lysosphingolipid
  • siponimod