Overview of FTY720 Clinical Pharmacokinetics and Pharmacology

Abstract

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.

Sphingosine and Its Analog, the Immunosuppressant 2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, Interact with the CB1 Cannabinoid Receptor

“…Therefore, administration of 10 mg/kg FTY720 would be expected to result in a concentration of approximately 1 M of FTY720 and phospho-FTY720. Similar results were reported in humans administered 5 mg/kg FTY720 for 7 days (Kovarik et al, 2004). These data showed that administration of FTY720 produced equal levels of FTY720 and phospho-FTY720 in the blood over the 24-h period monitored after drug administration.…”

Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies

“…37 ).The S1P analog FTY-720 is a functional antagonist of S1P activity as it binds to and downregulates expression of S1P receptors ( 38 ). These results in a transient, ‫ف‬ 40% decrease in peripheral blood lymphocyte counts ( 39 ). In this report, we have also shown that treatment of mice with anti-S1P mAbs transiently depletes peripheral blood lymphocytes in a fashion similar to that observed with FTY-720.…”

FTY720, a Synthetic Sphingosine 1 Phosphate Analogue, Inhibits Development of Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

“…20 This compound shows few toxic effects in either animal or human studies. 21,22 Accordingly, no adverse effects or significant changes in body weight were observed in the present investigation in treated animals during the FTY720-application period. Because of rapid initial absorption (time of occurrence for maximum drug concentration Ϸ2 to 24 hours), extensive volume of distribution, and exceptionally long elimination half-life (Ϸ7 days), FTY720 blood concentrations remain stable after administration, with little fluctuation during the dosing interval.…”

“…Because of rapid initial absorption (time of occurrence for maximum drug concentration Ϸ2 to 24 hours), extensive volume of distribution, and exceptionally long elimination half-life (Ϸ7 days), FTY720 blood concentrations remain stable after administration, with little fluctuation during the dosing interval. [21][22][23] Consistent with these pharmacokinetic properties, twice-or thrice-weekly administration of FTY720 is sufficient to suppress inflammatory processes in various mouse models. 24,25 In the present study, we found that repeated intraperitoneal injection of the compound (20 g/LDL-R Ϫ/Ϫ mouse, thrice weekly) produces FTY720 plasma concentrations of 67.5Ϯ8.7 ng/mL, which is within the known therapeutic concentration range.…”