Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients
Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients
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DOI：
10.1034/j.1600-6143.2003.00130.x
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发表时间：
2003-07-01
影响因子：
8.8
通讯作者：
Neumayer, HH
中科院分区：
文献类型：
--
作者：
Budde, K;Schmouder, RL;Neumayer, HH
FTY720是一种新的有效的免疫抑制剂，在动物模型中导致外周血淋巴细胞所有亚群的快速、可逆减少，诱导它们向次级淋巴器官迁移。在这项人体I期试验中，对单剂量口服FTY720的药效学进行了评估。一项随机、双盲、安慰剂对照、时滞研究对接受基于环孢素的方案的稳定肾移植患者进行了6种不同的单次口服FTY720剂量从0.25到3.5 mg不等的研究。在筛查和此后的多个时间间隔，通过血细胞计数和流式细胞术测定淋巴细胞和亚群的绝对计数以及白细胞的绝对分类计数。建立了药效学模型。24次单剂FTY720在4小时内引起一过性、可逆性泛淋巴细胞减少症。淋巴细胞亚群分析显示，几乎所有亚群都有所下降，其中CD4和CD45RA阳性细胞受到的影响最大。FTY720对自然杀伤细胞、粒细胞和单核细胞无明显影响。除最高剂量组外，其余各剂量组的淋巴细胞计数均在72小时内恢复到基线水平。药代动力学/药效学模型揭示了非线性剂量效应，结果与观测值吻合良好。这些数据表明，FTY720对人类非常有效，单剂量口服FTY720从0.25毫克到3.5毫克不等，会导致可逆性选择性全淋巴细胞减少症。
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 4h. 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 72h 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.