单剂量FTY720在健康受试者中的药代动力学、食物影响及药理反应。
Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects.
作者信息
Kovarik John M, Schmouder Robert, Barilla Denise, Wang Yibin, Kraus Gerolf
机构信息
Novartis Pharmaceuticals, Basel, Switzerland.
出版信息
Br J Clin Pharmacol. 2004 May;57(5):586-91. doi: 10.1111/j.1365-2125.2003.02065.x.
AIMS
FTY720 is a sphingosine-1-phosphate receptor agonist that redirects lymphocytes from the circulation to lymph nodes without impairing lymphocyte function. It is being developed as an immunomodulator for the prevention of acute rejection after organ transplantation. This study was performed to provide guidance on administration with respect to meals and to measure pharmacologic responses in healthy subjects.
METHODS
In this randomized, two-period, crossover study, 14 healthy subjects received placebo on day -1 of each period with baseline circadian measurements of lymphocyte count and heart rate. Subjects subsequently received a single 1 mg oral dose of FTY720 on day 1 under fasting conditions and after a high fat meal. Blood FTY720 concentrations, lymphocyte count, and supine heart rate were assessed over an 8 day period after each FTY720 dose. The effect of food on FTY720 pharmacokinetics was assessed by standard bioequivalence testing.
RESULTS
Both the peak concentration (0.65 +/- 0.17 vs 0.64 +/- 0.18 ng ml(-1)) and total exposure (AUC 149 +/- 65 vs 139 +/- 43 ng ml(-1) h) did not differ significantly between fasting and fed states, respectively. The corresponding fed/fasting ratios and 90% confidence intervals were 1.00 (0.86, 1.17) for Cmax and 0.98 (0.86, 1.11) for AUC. Under both treatment conditions peripheral blood lymphocyte count decreased from baseline by 38 +/- 9% over the first 2 days postdose and then increased towards predose values over the subsequent week. Whereas a circadian rhythm in supine heart rate was preserved in the presence of FTY720, the heart rate vs time curve was shifted downwards by 10% over the first day postdose and then recovered to prestudy values by days 3-5 postdose. These changes were asymptomatic.
CONCLUSIONS
Single 1 mg doses of FTY720 were well tolerated in healthy subjects and elicited a moderate decrease in peripheral blood lymphocyte count and a transient decrease in heart rate consistent with its pharmacological mode of action. FTY720 may be administered without regard to the timing of meals or their fat content.
目的
FTY720是一种鞘氨醇-1-磷酸受体激动剂，可使淋巴细胞从循环系统重新定向至淋巴结，而不损害淋巴细胞功能。它正作为一种免疫调节剂进行研发，用于预防器官移植后的急性排斥反应。本研究旨在为FTY720在进餐相关给药方面提供指导，并测定健康受试者的药理反应。
方法
在这项随机、两阶段、交叉研究中，14名健康受试者在每个阶段的第-1天接受安慰剂，并进行淋巴细胞计数和心率的基线昼夜测量。受试者随后在第1天禁食条件下和高脂餐后接受单次1 mg口服剂量的FTY720。在每次FTY720给药后的8天内评估血液中FTY720浓度、淋巴细胞计数和仰卧心率。通过标准生物等效性试验评估食物对FTY720药代动力学的影响。
结果
禁食和进食状态下的峰浓度（分别为0.65±0.17 vs 0.64±0.18 ng ml⁻¹）和总暴露量（AUC 149±65 vs 139±43 ng ml⁻¹·h）均无显著差异。相应的进食/禁食比值及90%置信区间，Cmax为1.00（0.86，1.17），AUC为0.98（0.86，1.11）。在两种治疗条件下，给药后第1个2天外周血淋巴细胞计数较基线水平下降38±9%，随后在接下来的一周内回升至给药前水平。虽然在FTY720存在的情况下仰卧心率的昼夜节律得以保留，但心率-时间曲线在给药后第1天向下偏移10%，然后在给药后第3至5天恢复到研究前水平。这些变化均无症状。
结论
单次1 mg剂量的FTY720在健康受试者中耐受性良好，可引起外周血淋巴细胞计数适度下降及心率短暂下降，与其药理作用模式相符。FTY720给药无需考虑进餐时间或食物脂肪含量。
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