title: Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function.
abstract: The authors assessed the impact of severe hepatic impairment on the disposition of fingolimod--a sphingosine-1-phosphate receptor immunomodulator primarily metabolized by CYP4F2--in 6 patients and 6 matched healthy controls who received a single 5-mg oral dose. Compared with healthy controls, severe hepatic-impaired subjects had a doubled area under the concentration time curve (AUC) and 50% prolonged elimination half-life but a similar peak blood concentration. When these data were combined with those from a previous study in mild and moderate hepatic-impaired subjects, there were significant positive correlations between fingolimod AUC versus bilirubin (r = 0.683) and prothrombin time (r = 0.777) and a significant negative correlation versus albumin (r = 0.578), confirming the importance of liver function for fingolimod clearance. For patients with severe hepatic impairment (Child-Pugh class C), a standard first dose of fingolimod could be given followed by a maintenance dose that is reduced by half from the normal maintenance dose.
authors.affiliation: Novartis Pharma AG, Building WSJ 103.426, 4002 Basel, Switzerland.
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schmouder
authors.forename: Stefan
authors.initials: S
authors.lastname: Hartmann
authors.forename: Gilles-Jacques
authors.initials: GJ
authors.lastname: Riviere
authors.forename: Franck
authors.initials: F
authors.lastname: Picard
authors.forename: Brigitta
authors.initials: B
authors.lastname: Voss
authors.forename: Markus
authors.initials: M
authors.lastname: Weiss
authors.forename: Frank
authors.initials: F
authors.lastname: Wagner
authors.forename: Hartmut H-J
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers; D005260:Female; D000068876:Fingolimod Hydrochloride; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008111:Liver Function Tests; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011485:Protein Binding; D011517:Prothrombin Time; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D007155:Immunologic Factors; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D001663:Bilirubin