title: Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients.
abstract: FTY720, a new and potent immunosuppressant, causes in animal models a rapid, reversible reduction of all subsets of peripheral blood lymphocytes, inducing their migration to secondary lymphoid organs. In this human phase I trial, the pharmacodynamics of single oral doses of FTY720 were evaluated. A randomized, double-blind, placebo-controlled, time-lagged study of six different single ascending oral doses of FTY720 ranging from 0.25 to 3.5 mg was conducted in stable renal transplant patients receiving a cyclosporine-based regimen. Absolute and subset lymphocyte counts, as well as absolute differential leukocyte counts, were determined by differential blood counts and flow cytometry at screening and multiple intervals thereafter. A pharmacodynamic model was established. Twenty-four single doses of FTY720 that were administered caused a transient, reversible pan-lymphopenia within 4 h. Lymphocyte subgroup analysis revealed that almost all subsets declined, with CD4- and CD45RA-positive cells being affected the most. Natural killer cells, granulocytes and monocytes were not influenced by FTY720. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Pharmacokinetik/pharmacodynamic modelling revealed a nonlinear dose effect and resulted in a good fit with observed values. These data show that FTY720 is highly effective in humans, with single oral doses of FTY720 ranging from 0.25 to 3.5 mg causing a reversible selective panlymphopenia.
authors.affiliation: Department of Nephrology, Charité University Hospital, Berlin, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Robert
authors.initials: R
authors.lastname: L  Schmouder
authors.forename: Bjorn
authors.initials: B
authors.lastname: Nashan
authors.forename: Reinhard
authors.initials: R
authors.lastname: Brunkhorst
authors.forename: Peter
authors.initials: P
authors.lastname: W  Lücker
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayer
authors.forename: Laurence
authors.initials: L
authors.lastname: Brookman
authors.forename: Jerry
authors.initials: J
authors.lastname: Nedelman
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.forename: Torsten
authors.initials: T
authors.lastname: Böhler
authors.forename: Hans-Hellmut
authors.initials: HH
authors.lastname: Neumayer
mesh_terms: D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D016131:Lymphocyte Subsets / Q000187:drug effects; D008231:Lymphopenia / Q000378:metabolism; D011409:Propylene Glycols / Q000493:pharmacokinetics*; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine