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FTY720 Pharmacokinetics in Mild to Moderate Hepatic Impairment

From Novartis Pharmaceuticals, Basel, Switzerland, and East Hanover, New Jersey (Dr Kovarik, Dr Schmouder, D. Serra, Dr Wang, Dr Wiegand) and Clinical Pharmacology Associates, Miami, Florida (S. C. Dilzer, Dr Lasseter).

The influence of mild and moderate hepatic impairment on FTY720 pharmacokinetics was assessed. The authors enrolled 32 subjects consisting of 8 with mild and 8 with moderate hepatic impairment based on Child-Pugh criteria and 16 demographically matched control subjects. A single 1-mg oral dose of FTY720 was administered under fasting conditions. Blood, plasma, and urine samples were obtained over a 14-day period for measurement of FTY720 and metabolite concentrations and protein binding. Total blood lymphocyte counts and heart rate were serially monitored to assess pharmacologic responses to FTY720. Peak FTY720 blood concentrations were similar across groups. Oral clearance (CL/F) was reduced 10% in mild hepatic impairment (P = .493) and 31% in moderate hepatic impairment (P = .034). There were no significant differences in blood exposure to the hexanoic or butanoic acid metabolites among groups. The effect of FTY720 on blood lymphocytes was similar across groups, with a mean decrease of 44% from the predose value. Like-wise, the effect of FTY720 on supine heart rate was similar across groups, with a mean 13% decrease from the predose rate occurring 2 to 4 hours postdose and recovering within 1 to 2 days. Although hepatic impairment elicited changes in the disposition of FTY720, the magnitude of these changes suggests that the FTY720 dose does not need to be adjusted in mild or moderate hepatic-impaired patients.

Key Words: FTY720 • hepatic impairment • drug metabolism

Address for reprints: J. M. Kovarik, PhD, FCP, Novartis Pharma, Building WSJ 27.P081, 4002 Basel, Switzerland.

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