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 h...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2006-02, Vol.46 (2), p.149-156
Main Authors: Kovarik, John M., Schmouder, Robert L., Hartmann, Stefan, Riviere, Gilles-Jacques, Picard, Franck, Voss, Brigitta, Weiss, Markus, Wagner, Frank, Schmidt, Hartmut H.-J.
Format: Article
Language:English
Subjects:
Adult
Area Under Curve
Bilirubin - blood
Biomarkers
Dosage and administration
dose adjustment
Drug therapy
Female
Fingolimod
Fingolimod Hydrochloride
Half-Life
Heart Rate - drug effects
hepatic impairment
Humans
Immunologic Factors - pharmacokinetics
Immunologic Factors - therapeutic use
immunosuppression
Liver diseases
Liver Diseases, Alcoholic - drug therapy
Liver Diseases, Alcoholic - metabolism
Liver Diseases, Alcoholic - physiopathology
Liver Function Tests
Lymphocyte Count
Male
Middle Aged
Multiple sclerosis
Pharmacokinetics
Propylene Glycols - pharmacokinetics
Propylene Glycols - therapeutic use
Protein Binding
Prothrombin Time
Risk factors
Sphingosine - analogs & derivatives
Sphingosine - pharmacokinetics
Sphingosine - therapeutic use
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Summary: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.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270005283464