Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects
Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects
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DOI：
10.1111/j.1365-2125.2011.04137.x
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发表时间：
2012-05-01
影响因子：
3.4
通讯作者：
Huggins, John P.
中科院分区：
文献类型：
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作者：
Li, Gai Ling;Winter, Helen;Huggins, John P.
目的 评估 PF-04457845（一种口服脂肪酸酰胺水解酶 1 (FAAH1) 抑制剂）在健康受试者中的药理学和耐受性。方法进行了双盲、随机、安慰剂对照的单次和多次递增剂量研究以及开放标签、随机、食物效应研究。测量了血浆和尿液中的PF-04457845浓度、血浆脂肪酸酰胺浓度和人白细胞中的FAAH1活性。评估了耐受性，包括对认知功能的影响。结果 PF-04457845 被快速吸收（中位 t(max) 0.5-1.2 小时）。暴露量与剂量成比例增加，从 0.1 至 10 mg，单剂量按比例增加 10 至 40 mg。每日一次0.5至8mg剂量给药14天后，药代动力学显示与剂量成正比。第 7 天达到稳态。不到 0.1% 的剂量通过尿液排出。食物对 PF-04457845 药代动力学没有影响。每日一次至少 0.3 mg（单剂量）和 0.5 mg（多剂量）PF-04457845 剂量后，FAAH1 活性几乎完全被抑制（> 97%）。 PF-04457845 后，平均脂肪酸酰胺浓度增加（3.5 至 10 倍）至稳定水平，然后保持不变。停止服用 4mg 剂量后，FAAH1 活性和脂肪酸酰胺浓度在 2 周内恢复到基线。没有证据表明 PF-04457845 对认知功能有影响。 PF-04457845，单剂量高达 40 mg 和每天一次 8 mg，持续 14 天，耐受性良好。结论 PF-04457845 在超过最大抑制 FAAH1 活性和升高脂肪酸酰胺所需剂量时具有良好的耐受性。
AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects. METHODS Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. RESULTS PF-04457845 was rapidly absorbed (median t(max) 0.5-1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (> 97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5-to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8mg once daily for 14 days, was well tolerated. CONCLUSIONS PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.