Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis
Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis
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DOI：
10.1016/j.jcf.2019.08.020
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发表时间：
2020-03-01
影响因子：
5.2
通讯作者：
Chevalier, E.
中科院分区：
文献类型：
--
作者：
Barth, P.;Bruijnzeel, P.;Chevalier, E.
背景：POL6014 是一种新型口服吸入中性粒细胞弹性蛋白酶 (NE) 抑制剂，正在开发用于治疗囊性纤维化 (CF)。方法：进行了两项研究，一项在健康志愿者中（HV，剂量 20 至 960 mg），另一项在 CF 受试者中（剂量 80 至 320 mg），以评估单次递增剂量吸入的安全性、耐受性和药代动力学 (PK) POL6014 配有 Pari eFlow (R) 雾化器。 PK 在 24 小时内进行评估。此外。测量了痰液中的 NE 活性。结果：单次给药后，对于 CF 受试者，POL6014 高达 480 mg 的 HV 剂量和所有剂量都是安全的且耐受性良好。 POL6014 在两个群体中均显示出剂量线性 PK 曲线，HV 受试者的 C-max 介于 0.2 至 2.5 μM 之间，CF 受试者中 C-max 介于 0.2 至 0.5 μM 之间。大约 2-3 小时达到 T-max。 CF痰中的平均POL6014水平迅速达到1000μM，并且在24小时时仍高于10μM。给药后 3 小时观察到活性 NE 减少超过 1 个对数。结论：吸入 POL6014 可以安全地导致肺内高浓度，同时血浆浓度较低，从而可以在单次给药后明显抑制 CF 受试者痰液中的 NE。 (C) 2019 Santhera 制药公司。由 Elsevier B.V. 代表欧洲囊性纤维化协会出版。
Background: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF).Methods: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow (R) nebuliser. PK was evaluated over a period of 24 h. In addition. NE activity in a sputum was measured.Results: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with C-max between 0.2 and 2.5 mu M in HVs and between 0.2 and 0.5 mu M in subjects with CF. T-max was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 mu M and were still above 10 mu M at 24 h. >1-log reduction of active NE was observed at 3 h after dosing.Conclusion: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. (C) 2019 Santhera Pharmaceuticals. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.