title: Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study .
abstract: OBJECTIVE
  To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected inactive metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS).
  
  
  METHODS
  The study enrolled subjects with severe RI (n = 8) and matched HS (n = 8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥ 50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects vs. HS. All subjects received a single oral dose of siponimod 0.25 mg on day 1; PK and safety were evaluated during the follow-up (~ 13 days).
  
  
  RESULTS
  PK of siponimod was marginally affected in severe RI subjects vs. HS: Cmax decreased by 8%, and AUClast and AUCinf increased by 23% and 24%, respectively; half-life (37 vs. 26 hours) and systemic clearance (2.9 vs. 3.4 L/h) were comparable. Siponimod plasma unbound (u) fraction at 4 hours post-dose was similar between the two groups (range: 0.0172 - 0.0550%). Cmax(u) was comparable while AUClast(u) and AUCinf(u) were increased by 33% compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment (RI) compared with matched HS. No adverse events were reported during this study.
  
  
  CONCLUSIONS
  Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further to severe RI, investigation of PK in subjects with mild and moderate RI was not warranted. .
authors.forename: Anne
authors.initials: A
authors.lastname: Gardin
authors.forename: Angela
authors.initials: A
authors.lastname: Dodman
authors.forename: Sampath
authors.initials: S
authors.lastname: Kalluri
authors.forename: Srikanth
authors.initials: S
authors.lastname: Neelakantham
authors.forename: Xuemei
authors.initials: X
authors.lastname: Tan
authors.forename: Eric
authors.initials: E
authors.lastname: Legangneux
authors.forename: Kasra
authors.initials: K
authors.lastname: Shakeri-Nejad
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; D006801:Humans; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D051437:Renal Insufficiency / Q000097:blood / Q000175:diagnosis / Q000378:metabolism*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D049349:Receptors, Lysosphingolipid; C578989:siponimod