Phase I Studies of Acebilustat: Pharmacokinetics, Pharmacodynamics, Food Effect, and CYP3A Induction.
Phase I Studies of Acebilustat: Pharmacokinetics, Pharmacodynamics, Food Effect, and CYP3A Induction.
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DOI：
10.1111/cts.12426
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Springman EB
中科院分区：
文献类型：
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作者：
Elborn JS;Bhatt L;Grosswald R;Ahuja S;Springman EB
Acebilusat 是一种新型每日一次口服抗炎药，正在开发中，用于治疗囊性纤维化 (CF) 和其他疾病。它是白三烯A4水解酶的抑制剂；因此，生物体液中白三烯 B4 (LTB4) 的产生提供了对 acebilustat 治疗的药效 (PD) 反应的直接测量。在这里，我们比较了 CF 患者和健康志愿者之间的药代动力学 (PK) 和 PD，并研究了健康志愿者中的食物效应和 CYP3A4 诱导。研究人群之间的峰值血浆水平 (Cmax) 或暴露量 (AUC) 没有观察到显着差异。在健康志愿者中，高脂肪餐后观察到 Cmax (Tmax) 的时间发生变化，但 AUC 没有变化。两个人群的血液和 CF 患者的痰液中 LTB4 的产生均减少。 Acebilustat 不诱导 CYP3A4。这些结果支持每日一次口服 acebilustat 治疗 CF（剂量为 50 和 100 mg）的持续临床研究。
Acebilustat is a new once‐daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (Cmax) or exposure (AUC). In healthy volunteers, a shift in time to Cmax (Tmax) was observed after a high‐fat meal, but there was no change in AUC. LTB4 production was reduced in the blood of both populations and in sputum from CF patients. Acebilustat did not induce CYP3A4. These results support continued clinical study of once‐daily oral acebilustat in CF at doses of 50 and 100 mg.