Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients.
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Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. / Klemens, Budde; Robert, L Schmouder; Nashan, Björn; Brunkhorst, Reinhard; Peter, W Lücker; Mayer, Thomas; Brookman, Laurence; Nedelman, Jerry; Skerjanec, Andrej; Böhler, Torsten; Neumayer, Hans-Hellmut.
in: AM J TRANSPLANT, Jahrgang 3, Nr. 7, 7, 2003, S. 846-854.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients.
AU - Klemens, Budde
AU - Robert, L Schmouder
AU - Nashan, Björn
AU - Brunkhorst, Reinhard
AU - Peter, W Lücker
AU - Mayer, Thomas
AU - Brookman, Laurence
AU - Nedelman, Jerry
AU - Skerjanec, Andrej
AU - Böhler, Torsten
AU - Neumayer, Hans-Hellmut
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 3
SP - 846
EP - 854
JO - AM J TRANSPLANT
JF - AM J TRANSPLANT
SN - 1600-6135
IS - 7
M1 - 7
ER -