title: Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects.
abstract: OBJECTIVE
  To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects.
  
  
  METHODS
  Healthy subjects (n=76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1). Pharmacokinetic and safety parameters were also assessed.
  
  
  RESULTS
  Siponimod and propranolol when administered alone resulted in similar HR decrease at steady state. Compared to propranolol alone, the combination at steady state had an additional 6.21 bpm (95%CI: 2.32, 10.11) decrease of mean EmaxHR, a decrease of 5.04 bpm (0.52, 9.56) for group A and 7.39 bpm (2.87, 11.90) for group B. A minor decrease in MABP and a trend towards PR interval increase were noted with co-administration treatment vs. propranolol alone. There were no episodes of second-degree atrioventricular blocks or sinus pauses>3 seconds. Baseline-corrected FEV1 was reduced by -0.07 L (95% CI: -0.17, 0.03) for group A and -0.05 L (-0.15, 0.05) for group B vs. propranolol alone. There were no cardiovascular adverse events during coadministration treatment.
  
  
  CONCLUSIONS
  Coadministration of siponimod and propranolol was well tolerated. Bradyarrhythmic effects were less pronounced when propranolol was added to siponimod steady-state therapy compared with siponimod addition to propranolol.
authors: Shibadas
authors: S
authors: Biswal
authors: Florine
authors: F
authors: Polus
authors: Parsar
authors: P
authors: Pal
authors: Uday Kiran
authors: UK
authors: Veldandi
authors: Thomas C
authors: TC
authors: Marbury
authors: Robert
authors: R
authors: Perry
authors: Eric
authors: E
authors: Legangneux
mesh_terms: D000328:Adult; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011433:Propranolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D011433:Propranolol; C578989:siponimod