FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects

The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) were randomized to FTY720 1.25 mg or 5 mg or placebo administered once daily for 7 days. Continuous telemetry revealed an acute, dose-dependent decrease in mean heart rate (10-bpm decrease vs placebo) following the first dose of FTY720, with a nadir generally 4 hours postdose. Although a persistent FTY720-related decrease in heart rate was measured from day 2 to day 7, additional doses of FTY720 after day 2 resulted in no further incremental decreases. Mean PR interval increased by approximately 8 to 10 msec in FTY720-treated subjects on day 1. FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect.     

FTY720 pharmacokinetics in mild to moderate hepatic impairment

The influence of mild and moderate hepatic impairment on FTY720 pharmacokinetics was assessed. The authors enrolled 32 subjects consisting of 8 with mild and 8 with moderate hepatic impairment based on Child-Pugh criteria and 16 demographically matched control subjects. A single 1-mg oral dose of FTY720 was administered under fasting conditions. Blood, plasma, and urine samples were obtained over a 14-day period for measurement of FTY720 and metabolite concentrations and protein binding. Total blood lymphocyte counts and heart rate were serially monitored to assess pharmacologic responses to FTY720. Peak FTY720 blood concentrations were similar across groups. Oral clearance (CL/F) was reduced 10% in mild hepatic impairment (P = .493) and 31% in moderate hepatic impairment (P = .034). There were no significant differences in blood exposure to the hexanoic or butanoic acid metabolites among groups. The effect of FTY720 on blood lymphocytes was similar across groups, with a mean decrease of 44% from the predose value. Like-wise, the effect of FTY720 on supine heart rate was similar across groups, with a mean 13% decrease from the predose rate occurring 2 to 4 hours postdose and recovering within 1 to 2 days. Although hepatic impairment elicited changes in the disposition of FTY720, the magnitude of these changes suggests that the FTY720 dose does not need to be adjusted in mild or moderate hepatic-impaired patients.     

Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects

OBJECTIVE: The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration. METHODS: In this randomized, two-period crossover study 11 evaluable healthy subjects received single doses of fingolimod 1.25 mg orally and 1 mg intravenously infused over 2 h. The pharmacokinetics of fingolimod, blood lymphocyte counts and heart rate were characterized for 28 days after each dose. RESULTS: After oral administration, Cmax was 1.1+/-0.2 ng/ml occurring at 12 h postdose and the AUC was 201+/-31 ng.h/ml. After intravenous infusion, Cmax was 4.9+/-0.8 ng/ml, AUC was 175+/-50 ng. h/ml, clearance was 6.3+/-2.3 l/h and distribution volume was 1199+/-260 l. The oral/intravenous ratio of dose-normalized AUCs was 0.94 (95%CI: 0.78-1.12). The pharmacologically active metabolite fingolimod-phosphate was quantifiable near its peak after oral administration but not after intravenous administration. The mean lymphocyte nadir occurred on day 1 and was 35% lower after oral (0.74x10(9)/l) than after intravenous (1.15x10(9)/l) administration. Lymphocytes recovered to the normal range by day 15 for both treatments. The mean heart rate nadir occurred 3-4 h postdose and was 11% lower after oral administration (47 bpm) versus intravenous administration (53 bpm). CONCLUSIONS: Average systemic exposure to fingolimod was similar after oral and intravenous administration. However, the acute decrease in lymphocyte counts was weaker after intravenous administration, likely because of lower blood levels of the active metabolite fingolimod-phosphate compared with oral administration.     

Overview of FTY720 clinical pharmacokinetics and pharmacology

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.     

芬戈莫德干预大鼠抗Thy-1系膜增生性肾炎的研究

目的:观察芬戈莫德(FTY720)对淋巴细胞亚群的影响,并藉此在体内发挥抑制大鼠系膜增生和系膜基质扩张的作用。方法:通过一次性注射抗Thy-1抗体制备大鼠抗Thy-1系膜增生性肾炎模型,同时给予FTY720灌胃干预,观察注射后1,3,7 d大鼠外周血淋巴细胞计数和亚群分类、尿蛋白定量、肾小球系膜增生程度。结果:在注射抗体1 d后,模型组即出现蛋白尿,3 d后可见系膜细胞和基质增生,7 d增生最明显。FTY720干预组在1,3,7 d后均能显著减少外周血淋巴细胞和各淋巴细胞亚群数量;在注射后3 d和7 d,FTY720可以显著减少模型大鼠蛋白尿,减轻肾小球系膜增生程度和细胞外基质扩张。结论:FTY720可以影响外周血淋巴细胞数量和淋巴细胞亚群分布,显著减少模型大鼠蛋白尿,减轻模型大鼠系膜增生和系膜基质扩张,干预抗Thy-1系膜增生性肾炎的发生。     

S1P1受体激动剂FTY720的免疫抑制作用

FTY720(2-amino-2-[2-(4-octylphenyl)ethyl]-l,3-propanediol hydrochloride,图1)是日本京都大学的藤多哲朗教授等从寄生蝉幼虫的子囊菌(Isariasinclairii)培养液中提取的抗生素成分。ISP-1(myriocin/thermozymocidin)是经化学结构修饰后得到的合成药物[1],在细胞内被鞘氨醇激酶2(sphingosinekinase 2,Sphk2)磷酸化为具有生物活性的FTY720-P。     

Ethnic sensitivity study of fingolimod in white and Asian subjects

OBJECTIVE: The authors compared the pharmacokinetics and pharmacological effects of the immunomodulator fingolimod in healthy white and Asian subjects for potential ethnic differences. METHODS: White and Asian (Japanese) healthy subjects were demographically matched for sex, age and weight. Subjects received single 1.25 mg doses of fingolimod (6 ethnic pairs), 2.5 mg (7 pairs), 5 mg (6 pairs) or 5 mg/day for 7 days (6 pairs). The pharmacokinetics of fingolimod, major metabolites, peripheral blood lymphocyte counts and heart rate were characterized over 1 month after single-dose and 2 months after multiple-dose administration. RESULTS: There were no clinically relevant differences in the fingolimod dose Cmax or dose AUC relationships between Asian subjects (slopes 0.84 and 1.05) versus white subjects (slopes 1.13 and 1.26) after single-dose administration. During multiple-dose administration, there were no clinically relevant interethnic differences in fingolimod accumulation ratios (6.6 +/- 0.4 for whites, 7.0 +/- 0.7 for Asians), area under the concentration-time curve (390 +/- 73 versus 382 +/- 106 ng x h/ml), or elimination half-life (7.4 +/- 0.8 versus 7.9 +/- 2.0 days). The acute decrease in lymphocyte counts after single- and multiple-dose fingolimod were similar in the two ethnic groups. The lymphocyte recovery rate to baseline after a 5 mg single dose and 5 mg/day multiple dose was reduced by 36 and 15% in Asian subjects compared with white subjects. The transient, acute decrease in heart rate after the first dose of fingolimod and the subsequent return to baseline was similar in the two ethnic groups. CONCLUSION: There were no marked differences between healthy white and Asian subjects in fingolimod single-dose and multiple-dose pharmacokinetics, lymphocyte trafficking and heart rate responses.     

FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes

FTY720 is a new immunosuppressant agent and selectively decreases the number of circulating lymphocytes. In this study, we compared the effects of FTY720 with those of tacrolimus on experimental autoimmune myocarditis (EAM) in rats. A significant decrease in circulating lymphocyte counts was noted after a single administration of FTY720 in normal rats. At day 0, 7-week-old male Lewis rats were immunized with purified porcine cardiac myosin emulsified in complete Freund's adjuvant. FTY720 or tacrolimus was administered intraperitoneally daily. The number of myocarditis-affected areas in the FTY720 treatment groups with doses of 0.1 mg/kg/ day was significantly lower than those in control groups at days 14 and 28. In addition, at day 28, the myocarditis-affected areas in the FTY720 treatment group were significantly smaller than those in the tacrolimus treatment group receiving the same dose. Effects of early administration (days 0-10) and delayed administration (days 11-20) of FTY720 also were examined. At day 28, the myocarditis-affected areas in the early therapy group were significantly lower than those in the control group. In conclusion, we demonstrated that the development of EAM could be prevented by FTY720. These data also indicated that lymphocyte-mediated immunity is critically involved in the development of EAM.     

A mechanistic study to assess whether isoproterenol can reverse the negative chronotropic effect of fingolimod

The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) elicits a negative chronotropic effect at treatment initiation that attenuates thereafter. The authors determined whether isoproterenol can counteract this effect. In this randomized, crossover study, 14 healthy subjects received 5 infusions of isoproterenol (titrated to increase heart rate to 100-120 bpm) or intravenous placebo. The first infusion was 2 hours before and the other 4 infusions were between 3 and 6 hours after a 5-mg oral dose of fingolimod. Telemetry and pharmacokinetic data were collected for 24 hours. During isoproterenol infusion 1 (before fingolimod administration), heart rate was increased 80% from preinfusion 68 +/- 9 bpm to a maximum 122 +/- 15 bpm. Administration of fingolimod decreased heart rate from 73 +/- 11 bpm predose to a nadir of 57 +/- 8 bpm. The subsequent isoproterenol infusion 2 in the presence of fingolimod increased mean heart rate by 85% to a maximum 105 +/- 21 bpm. A 41% higher total isoproterenol dose was needed to increase heart rate to the target range with fingolimod (97 +/- 6 mcg) compared with isoproterenol alone (69 +/- 27 mcg). Isoproterenol infusions 3 to 5 had similar effects on heart rate as infusion 2. Fingolimod had no significant influence on blood pressure responses to isoproterenol. Isoproterenol did not alter the pharmacokinetics of fingolimod. The pure beta-agonist isoproterenol can reverse the heart rate reduction that occurs transiently after initiating fingolimod treatment.     

一种新的免疫抑制剂FTY720对小鼠心脏移植的救治作用(英文)

AIM: FTY720 is a new synthetic immunosuppressive agent which has a unique mechanism of action and induces long-term graft acceptance in rat and dog allotransplantation as prophylactic administration. The present study investigated whether FTY720 was able to rescue ongoing acute rejection of solid organ transplants in a mouse heterotopic cardiac transplantation model. METHODS: BALB/c hearts were heterotopically grafted in C57BL/6 mice. FTY720, at the doses of 0.5, 1, and 5 mg·kg~(-1)·d~(-1) or vehicle was administered to recipients once daily by oral gavage from d 3 to d 7 after transplantation. Histological changes of grafts, and the lymphocyte number in the peripheral blood and the peripheral lymph nodes were determined on d 5 after transplantation. RESULTS: FRY720 prolonged the median graft survival time dose-dependently and significantly. Histological evaluation revealed less lymphocytic infiltration in cardiac allografts treated with FTY720. Moreover, FTY720 remarkably lowered the number of periph     

Pharmacodynamics of FTY720, the first member of a new class of immune-modulating therapeutics in transplantation medicine

FTY is a novel immunomodulator currently undergoing clinical investigation and has the potential of improving immunosuppressive therapy after organ transplantation. Previous experimental studies in animals have shown that FTY has a unique mechanism of action. We have studied the pharmacodynamic effects of FTY in stable renal allograft recipients taking part in a phase I clinical trial. As in various animal models including non-human primates, a single oral dose of FTY (0.25 - 3.5 mg) significantly reduced peripheral lymphocyte count by 30 - 70%. The peripheral lymphocyte count returned to baseline within 24 hours. Only in those patients treated with the highest dose of FTY (3.5 mg), did peripheral lymphopenia persist for more than 96 hours. FTY reduced all lymphocyte subsets, T cells more than B cells and CD4+ cells more than CD8+ cells. The reduction in CD3+CD62L+ cell counts was more pronounced, whereas CD3+CCR5+ cell counts were less affected in comparison to the total number of CD3+ lymphocytes. We found only slightly increased apoptosis rates (< 5%) in peripheral lymphocytes, and this change does not explain the marked reduction in lymphocyte count. In cultured human lymphocytes only suprapharmacological doses of 10 microM FTY induced apoptosis (20.6 +/- 2.8%) after a 4-h incubation. More important, clinically relevant doses of 0.1 microM FTY increased lymphocyte mobility 2-fold. No effect of FTY on anti-CD3mAb-stimulated lymphocyte proliferation was detected and there was no change in phagocytosis rates in whole-blood cultures incubated with FTY. Further studies are necessary to investigate the mechanism of action of FTY in detail.     

Differential effects of single dose FTY720 on CD62L+ B-cells in stable renal allograft recipients

FTY720, a sphingosine-1-phosphate receptor agonist, is the archeotype of a new class of immune modulators, which redirects lymphocytes from the peripheral blood into secondary lymphatic tissue. Previously, it was shown that FTY720 differentially decreases peripheral T-cells, expressing specific chemokine and adhesion receptors. Here, we investigated the effect of single doses FTY720 on peripheral B-cells expressing CD62L, CD11a, CD49d and CXCR4 in stable human renal allograft recipients. Peripheral blood lymphocytes were isolated by Ficoll density centrifugation and stained with monoclonal antibodies against CD3 or CD19 and CD62L, CD11a, CD49d, CXCR4 to determine the percentage of these T- and B-cell subpopulations. Total lymphocyte counts were measured by routine laboratory diagnostics to calculate absolute lymphocyte subset counts. In FTY720 treated patients, total lymphocyte counts decreased by 31.8% (0.25-2 mg) and 60.4% (3.5 mg), and total T-cell counts by 38.8% (0.25-2 mg) and 70.9% (3.5 mg). In comparison, total B-cell counts decreased by 32.2% (0.25-2 mg) and 61.1% (3.5 mg). The reduction of CD62L+ B-cells was less pronounced as compared to CD62L+ T-cells (0.25-2 mg: 15.7% vs. 57.3%; 3.5 mg: 57.2% vs. 86.9%). CD11a+ B-cells decreased by 15.4% (0.25-2 mg) and 57.1% (3.5 mg), and CD49d+ B-cells by 15.0% (0.25-2 mg) and 56.7% (3.5 mg). CXCR4+ B-cells decreased by 19.9% (0.25-2 mg) and 57.2% (3.5 mg). In vitro experiments showed that FTY720 did not change the mean expression of CD62L, CD11a, CD49d and CXCR4 on CD19+ B-cells. In conclusion FTY720 treatment reduces B-cells expressing CD62L to a significant lesser degree than T-cells expressing CD62L.     

Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy

T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model. FTY720 (0.3 mg/kg/day) was administered intraperitoneally daily for the first 4 weeks with interim 3 weeks then resumed for another 4 weeks in 11 weeks study period. T lymphocyte counts, cardiac histology, function, and fibrosis were examined in diabetic both WT and KO mice. FTY720 reduced both CD4⁺ and CD8⁺ T cells in diabetic WT mice. FTY720-treated diabetic WT mouse myocardium showed reduction in CD3 T cell infiltration and decreased expression of S1P₁ and TGF-β1 in cardiac tissue. Fibrosis was reduced after FTY720 treatment in diabetic WT mice. Rag1 KO mice exhibited no CD4⁺ and CD8⁺ T cells in the blood and CD3 T cells in the heart. Diabetic Rag1 KO mouse hearts appeared no fibrosis and exhibited preserved myocardial contractility. FTY720-induced antifibrosis was abolished in diabetic Rag1 KO mice. These findings demonstrate that chronic administration with FTY720 induces lymphopenia and protects diabetic hearts in WT mice whereas FTY720 increases cardiac fibrosis and myocardial dysfunction in diabetic Rag1 KO mice without mature lymphocytes.     

Evidence that FTY720 induces T cell apoptosis in vivo

The immunosuppressant FTY720 induces a drastic decrease in blood lymphocytes, especially T cells; a decrease which is assumed to be the immunosuppressive mechanism of this drug. FTY720 causes cell death in vitro in lymphocytes and leukemia cells. However, the deletion mechanism of blood lymphocytes in vivo remains unclear. We investigated whether administration of FTY720 induced lymphocyte apoptosis in blood circulation. A marked decrease in the number of blood lymphocytes was observed within an hour after a single oral administration of FTY720 at doses of 5-10 mg/kg in rats and mice. Experiments using fluorescein isothiocyanate (FITC)-Annexin V and APO-BRDU methods revealed that FTY720 induced blood lymphocyte apoptosis in a dose-dependent manner. On the other hand, lymphocyte homing to Peyer's patches was proposed as the mechanism underlying the blood lymphocyte decrease at these doses. However, similar results were obtained when using aly/aly mice, which lack Peyer's patches and lymph nodes. Thus, we concluded that apoptosis of blood lymphocytes was induced immediately after administration of FTY720, and the cells could be immediately scavenged by phagocytes or the reticuloendothelial system in addition to Peyer's patches homing. We also concluded that T cells were highly sensitive to FTY720, which induced apoptosis in vivo.     

Analysis of the mode of action of a novel immunosuppressant FTY720 in mice.

Accelerated lymphocyte homing and apoptosis have been suggested to contribute to potent immunosuppressive effects of FTY720, however, its main mechanism of action remains to be fully elucidated. Here, we examined the mode of action of FTY720 in mice. FTY720, when given at a single dose of 1 mg/kg, markedly decreased the number of peripheral blood lymphocytes (PBL) but moderately increased the lymphocyte numbers in lymph nodes (LN) and Peyer's patches (PP) in normal mice, as previously observed in rats. However, the sharp decrease in PBL numbers was also observed in aly/aly mice lacking LN and PP, indicating that this phenomenon is not explained by accelerated lymphocyte homing to LN and PP. In addition, the finding that a single administration of FTY720 did not suppress proliferative responses of T cells suggested that the PBL reduction could occur without inhibiting lymphocyte functions. However, when administered at the same dose for 2 weeks, FTY720 induced severe systemic lymphopenia, as well as marked suppression of lymphocyte proliferative responses in normal mice. The same treatment also prolonged skin allograft survival in aly/aly mice. Our results suggest that FTY720 suppresses in vivo immune functions mainly by inducing systemic lymphopenia and also by inhibiting T cell functions.     

An assessment of the contribution of clonidine metabolised from alinidine to the cardiovascular effects of alinidine.

Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2-7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/- 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/- 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/- 0.15 and 0.86 +/- 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/- 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/- 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

FTY720对免疫性肝损伤保护作用的研究

目的　应用免疫性肝损伤模型研究FTY72 0对肝脏的保护作用并对其作用机制进行初步探讨。方法　分别以BCG +LPS和ConA诱导两种免疫性肝损伤模型并通过测定血清中ALT和AST水平的变化检测FTY72 0对两种肝损伤的保护作用。以ELISA方法测定血清中细胞因子IFN γ及IL 4水平的变化并应用淋巴细胞增殖实验检测FTY72 0对淋巴细胞增殖能力的影响。结果　FTY72 0可以使两种肝损伤模型中升高的血清ALT和AST水平下降 ,并可以降低肝损伤时血清中IFN γ及IL 4的水平 ,实验还证明FTY72 0可以抑制淋巴细胞的增殖。结论　FTY72 0预防应用对免疫性肝损伤有保护作用 ,其保肝作用机制可能和抑制淋巴细胞的增殖 ,进一步抑制细胞因子的产生有关     

Pharmacological pre- and post-conditioning with the sphingosine-1-phosphate receptor modulator FTY720 after myocardial ischaemia�Creperfusion

Background and purpose:

Our recent experiments demonstrated that the Sphingosine-1-phosphate (S1P) receptor agonist FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) improves recovery of function after myocardial ischaemia–reperfusion ex vivo. Therefore, we tested the hypothesis that pharmacological post-conditioning with FTY720 reduces infarct size after myocardial ischaemia–reperfusion in vivo.

Experimental approach:

Myocardial ischaemia was induced in Wistar rats by ligation of the left coronary artery for 45 min. FTY720 (0.5 mg·kg⁻¹) was applied i.p. either once, before reperfusion, or twice, 24 h before myocardial ischaemia and before reperfusion. After 24 h reperfusion, we determined infarct size by triphenyltetrazolium chloride staining and granulocyte infiltration by immunohistochemistry. Tumour necrosis factor-α (TNF)-α concentration was determined by elisa. S1P receptor expression was studied by Western blot. Calcium transients were evaluated in Indo-1-loaded cardiomyocytes.

Key results:

In both groups, FTY720 significantly reduced lymphocyte count in peripheral blood. FTY720 treatment attenuated granulocyte infiltration and TNF-α protein expression in reperfused myocardium. However, both treatment regimens were not able to reduce infarct size. FTY720 increased mortality due to induction of fatal ventricular tachyarrhythmias when administered once before reperfusion, but protected against reperfusion arrhythmias when given 24 h prior to ischaemia. Pretreatment selectively down-regulated S1P₁ receptor expression within the myocardium. S1P receptor agonists did not induce calcium deregulation in cardiomyocytes.

Conclusions and implications:

FTY720 applied during reperfusion did not reduce infarct size but increased mortality during myocardial ischaemia–reperfusion due to induction of arrhythmias. Pretreatment with FTY720 before ischaemia abrogated the deleterious pro-arrhythmic effects without reducing infarct size.     

FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship

The pharmacokinetics, safety, and preliminary efficacy of FTY720, a novel immunomodulator, were examined in de novo renal transplant patients. Both noncompartmental and population methods were used to estimate pharmacokinetic estimates in the patients. The steady-state plasma concentrations of FTY720 increased in accordance with maintenance dose level, indicating linearity in clearance and volume of distribution over the 0.25- to 2.5-mg dose range. The pharmacokinetics of FTY720 in de novo renal transplant patients were characterized by the long terminal phase half-life of approximately 200 hours across doses, high volume of distribution (>3000 L), and low clearance (10.8 L/h). The intersubject variation of clearance was 55%, and the intrasubject variation of FTY720 concentrations was 28%. The population analysis revealed significant positive relationships between baseline alkaline phosphatase and clearance, as well as between baseline body weight on apparent volume of distribution. There was no relationship between FTY720 concentrations within a given FTY720 dose cohort and the rate of allograft rejection.