Pfizer Worldwide Research and Development, Sandwich, UK.
Br J Clin Pharmacol. 2012 May;73(5):706-16. doi: 10.1111/j.1365-2125.2011.04137.x.
AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects.
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.
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 8 mg. 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 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated.
PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.
评估 PF-04457845 的药理学和耐受性，PF-04457845 是一种口服可用的脂肪酸酰胺水解酶-1（FAAH1）抑制剂，在健康受试者中。
进行了双盲、随机、安慰剂对照的单剂量和多剂量递增研究以及开放标签、随机、食物效应研究。测量了人白细胞中 PF-04457845 的血浆和尿液浓度、血浆脂肪酸酰胺浓度和 FAAH1 活性。评估了耐受性，包括对认知功能的影响。
PF-04457845 吸收迅速（中位数 t(max)0.5-1.2 h）。从 0.1 至 10 mg 剂量呈超比例增加，10 至 40 mg 单剂量呈比例增加。14 天每天一次 0.5 至 8 mg 剂量后，药代动力学呈剂量比例。第 7 天达到稳态。少于 0.1%的剂量以尿液形式排泄。食物对 PF-04457845 的药代动力学没有影响。至少 0.3 毫克（单剂量）和 0.5 毫克（每天一次）PF-04457845 给药后，FAAH1 活性几乎完全被抑制（>97%）。PF-04457845 给药后，脂肪酸酰胺浓度升高（3.5-至 10 倍）至平台，然后维持。在剂量高达 4 毫克时，停止给药后 2 周内，FAAH1 活性和脂肪酸酰胺浓度恢复至基线。没有证据表明 PF-04457845 对认知功能有影响。在高达 40 毫克单剂量和 14 天每天 8 毫克的剂量下，PF-04457845 耐受性良好。
在超过 FAAH1 活性最大抑制和脂肪酸酰胺升高所需的剂量下，PF-04457845 耐受性良好。
