title: Absolute Bioavailability of Ponesimod, a Selective S1P1Receptor Modulator, in Healthy Male Subjects.
abstract: OBJECTIVE
  The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (tmax) of 2-4 h] and a terminal half-life (t½) of 32 h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (Vss)] in healthy male subjects.
  
  
  METHODS
  After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase.
  
  
  RESULTS
  The absolute bioavailability of ponesimod was 83.8 % [90 % confidence interval (CI): 80.2-87.5]. CL and Vss(95 % CI) were 3.8 L/h (3.3-4.3) and 160 L (146.1-174.2), respectively. Cmax(95 % CI) was 48.5 ng/mL (43.9-53.6) and 61.4 ng/mL (55.3-68.3) after intravenous infusion and oral administration, respectively. The t½(95 % CI) following intravenous infusion was 32.9 h (28.5-38.1) and 31.7 h (27.9-36.0) following oral administration. Ponesimod administered by both routes of administration was well tolerated and resulted in transient decreases in lymphocyte count and heart rate.
  
  
  CONCLUSIONS
  This study indicates high absolute bioavailability, low CL, and moderate Vssof ponesimod.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Margaux
authors.initials: M
authors.lastname: Boehler
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. pierre-eric.juif@actelion.com.
authors.forename: Pierre-Eric
authors.identifier: http://orcid.org/0000-0002-4899-8768
authors.initials: PE
authors.lastname: Juif
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoch
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod