Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function.
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.
Kovarik
John M
JM
Novartis Pharma AG, Building WSJ 103.426, 4002 Basel, Switzerland.
Schmouder
Robert L
RL
Hartmann
Stefan
S
Riviere
Gilles-Jacques
GJ
Picard
Franck
F
Voss
Brigitta
B
Weiss
Markus
M
Wagner
Frank
F
Schmidt
Hartmut H-J
HH
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
D015415:Biomarkers; D007155:Immunologic Factors; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D001663:Bilirubin