Kovarik John M, Hartmann Stefan, Bartlett Michael, Riviere Gilles-Jacques, Neddermann Daniel, Wang Yibin, Port Andreas, Schmouder Robert L
Novartis Pharmaceuticals, Basel, Switzerland.
Biopharm Drug Dispos. 2007 Mar;28(2):97-104. doi: 10.1002/bdd.535.
The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration.
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.
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).
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.
对免疫调节剂芬戈莫德（FTY720）口服和静脉给药后的药代动力学及淋巴细胞反应进行表征。
在这项随机、两期交叉研究中，11名可评估的健康受试者分别接受单剂量口服1.25mg芬戈莫德和静脉输注1mg芬戈莫德（2小时内输完）。每次给药后28天对芬戈莫德的药代动力学、血液淋巴细胞计数和心率进行表征。
口服给药后，Cmax为1.1±0.2ng/ml，于给药后12小时出现，AUC为201±31ng·h/ml。静脉输注后，Cmax为4.9±0.8ng/ml，AUC为175±50ng·h/ml，清除率为6.3±2.3l/h，分布容积为1199±260l。剂量标准化AUC的口服/静脉比值为0.94（95%CI：0.78 - 1.12）。具有药理活性的代谢产物磷酸芬戈莫德在口服给药后接近峰值时可定量，但静脉给药后不可定量。淋巴细胞最低点平均出现在第1天，口服给药后（0.74×10⁹/l）比静脉给药后（1.15×10⁹/l）低35%。两种治疗方法的淋巴细胞在第15天均恢复到正常范围。平均心率最低点出现在给药后3 - 4小时，口服给药后（47次/分钟）比静脉给药后（53次/分钟）低11%。
口服和静脉给药后芬戈莫德的全身平均暴露量相似。然而，静脉给药后淋巴细胞计数的急性下降较弱，可能是因为与口服给药相比，活性代谢产物磷酸芬戈莫德的血药水平较低。
