Multiple‐Dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects

Abstract

FTY720 is a sphingosine-1-phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple-dose FTY720. In this randomized, double-blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month-long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory E(max) model. First-dose exposure was consistent with dose proportionality between the low- and high-dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for C(max) (5.0 +/- 1.0 vs. 18.2 +/- 4.1 ng/mL) and for AUC (109 +/- 24 vs. 399 +/- 85 ng.h/mL). Washout pharmacokinetics after the last dose indicated an elimination half-life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 +/- 0.1 x 10(9)/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 +/- 0.1 x 10(9)/L. Descriptive exposure-response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end-of-study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low- and high-dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose-proportionality after both single- and multiple-dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure-response modeling provided evidence that 5 mg/day FTY720 resulted in a near-maximal dynamic effect of this drug on lymphocytes.

The Sphingosine-1 Phosphate receptor agonist FTY720 dose dependently affected endothelial integrity in vitro and aggravated ventilator-induced lung injury in mice

“…Different clinical studies analyzed FTY720 pharmacokinetics, pharmacodynamics [22] and the use of FTY720 for the treatment of graft rejection [3,5] or multiple sclerosis [6][7][8][9], and adverse effects related to impaired endothelial barrier integrity have not been reported. Notably, in none of these trials critically ill patients receiving MV were included.…”

“…Thus, accumulation of FTY720 is probable in patients with multiple organ dysfunction syndrome [22][23][24][25]. Considering the complex role of S1P receptor signaling in the regulation of endothelial barrier function, relevant risks for critically ill FTY720-treated patients need to be envisioned.…”

“…In humans FTY720 has an elimination half life of more than 8 days under 5 mg daily dosing, and a high volume of distribution exceeding 1000 l [22]. Hepatic impairment M A N U S C R I P T…”

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

“…15,16 Identification of new agents with reduced elimination half-life has been sought after, as full lymphocyte recovery following fingolimod treatment requires >5 weeks and could be a complicating factor in the event of opportunistic infection. 17 In addition, teratogenicity has been observed in rodents, and the long half-life in humans (8 days) requires contraception for two months after stopping treatment. 18 A further challenge is identifying therapeutics with appreciable central exposure as this is believed to be necessary for success in treating MS. 19 Lastly, new agents with reduced hepatotoxicity in humans would be highly beneficial.…”

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists

“…Correspondingly, normalization of lymphocyte levels requires >5 weeks following cessation of fingolimod treatment. 19 A shorter acting agent may be desirable in the event of an opportunistic infection where a rapid return to normal immune functioning would be advantageous. We, and others, have sought to avoid S1P 1 modulators requiring bioactivation (e.g., phosphorylation), instead focusing on carboxylates as phosphate mimetics.…”