title: Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.
authors: Novartis Pharma AG, Basel, Switzerland. eric.legangneux@novartis.com
authors: Eric
authors: E
authors: Legangneux
authors: Anne
authors: A
authors: Gardin
authors: Donald
authors: D
authors: Johns
mesh_terms: D000293:Adolescent; D000328:Adult; D001384:Azetidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001593:Benzyl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001919:Bradycardia / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D049349:Receptors, Lysosphingolipid; C578989:siponimod