Overview of FTY720 clinical pharmacokinetics and pharmacology.

Drug discovery programs are actively exploring for therapeutic agents targeting enzymes and receptors regulating sphingolipid metabolism and biologic functions. FTY720 is a close structural analogue of sphingosine with immunomodulatory properties. After oral administration, FTY720 is phosphorylated by sphingosine kinase to form the active moiety FTY720-phosphate, which subsequently binds to the sphingosine-1-phosphate receptor. In characterizing the safety and pharmacological effects of FTY720, detailed clinical pharmacology studies in healthy subjects and renal transplant recipients have focused on cardiac responses and lymphocyte trafficking. After the first dose, FTY720 causes a mild, transient decrease in heart rate that returns to baseline in approximately 1 to 2 weeks despite continued administration of the drug. FTY720 elicits a prompt and dose-dependent decrease in peripheral blood lymphocytes by redirecting them from the circulation to the lymph nodes without impairing lymphocyte functions. An association among FTY720 blood concentration, decrease in lymphocyte counts, and freedom from acute rejection episodes has been observed in early clinical development trials in de novo kidney transplantation.