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Fingolimod (FTY720) in Severe Hepatic Impairment: Pharmacokinetics and Relationship to Markers of Liver Function

From Novartis Pharmaceuticals, Basel, Switzerland, East Hanover, New Jersey, and Rueil-Malmaison, France (Dr Kovarik, Dr Schmouder, Dr Hartmann, Dr Riviere, Dr Picard, Dr Voss, Dr Weiss); 3ClinicalResearch, Henningsdorf, Germany (Dr Wagner); and Universitätsklinikum Charité, Berlin, Germany (Dr Schmidt).

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.

Key Words: Fingolimod • immunosuppression • hepatic impairment • dose adjustment

Address for reprints: John M. Kovarik, Novartis Pharma AG, Building WSJ 103.426, 4002 Basel, Switzerland.

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