title: Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study .
abstract: OBJECTIVE
  To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS).
  
  
  METHODS
  This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up.
  
  
  RESULTS
  All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings.
  
  
  CONCLUSIONS
  Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI. .
authors.forename: Kasra
authors.initials: K
authors.lastname: Shakeri-Nejad
authors.forename: Vassilios
authors.initials: V
authors.lastname: Aslanis
authors.forename: Uday Kiran
authors.initials: UK
authors.lastname: Veldandi
authors.forename: Anne
authors.initials: A
authors.lastname: Gardin
authors.forename: Andreas
authors.initials: A
authors.lastname: Zaehringer
authors.forename: Angela
authors.initials: A
authors.lastname: Dodman
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Su
authors.forename: Eric
authors.initials: E
authors.lastname: Legangneux
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001384:Azetidines / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001593:Benzyl Compounds / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D048550:Hepatic Insufficiency / Q000097:blood / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D049349:Receptors, Lysosphingolipid; C578989:siponimod