Mackie Alison, Rascher Juliane, Schmid Marion, Endriss Verena, Brand Tobias, Seibold Wolfgang
Boehringer Ingelheim, Biberach an der Riss, Germany.
SocraMetrics GmbH, Erfurt, Germany, on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
ERJ Open Res. 2021 Feb 1;7(1). doi: 10.1183/23120541.00447-2020. eCollection 2021 Jan.
Inhibition of the epithelial sodium channel (ENaC) represents a mutation-agnostic therapeutic approach to restore airway surface liquid hydration and mucociliary clearance in patients with cystic fibrosis. BI 1265162 is an inhaled ENaC inhibitor with demonstrated preclinical efficacy.
Three phase I trials of BI 1265162 in healthy male subjects are presented: NCT03349723 (single-rising-dose trial evaluating safety, tolerability and pharmacokinetics (PK)); NCT03576144 (multiple-rising-dose trial evaluating safety, tolerability and PK); and NCT03907280 (absolute bioavailability trial).
BI 1265162 single doses ≤1200 µg and multiple doses of 600 µg were well tolerated. Adverse events were balanced across treatment groups, were of mainly mild or moderate intensity and resolved by trial-end. One subject discontinued from trial medication on day 7 (asymptomatic hyperkalaemia adverse event; recovered day 8). One subject experienced a serious adverse event (neuropathia vestibularis) leading to hospitalisation and missed one of the four dosing periods. Both events were not considered to be drug-related and subjects recovered. BI 1265162 displayed dose-proportional, time-independent PK; maximum accumulation was 1.6-fold; calculated effective elimination half-life was 3.6-8.7 h over the dose ranges tested. Renal excretion was not a major drug elimination route. Oral and inhaled dosing (±activated oral charcoal) absolute bioavailability was 0.50% and ∼40%, respectively.
BI 1265162 single or multiple doses up to 6.5 days were well tolerated. Systemic exposures mainly represent drug absorbed through the lungs and not the gastrointestinal tract, with ∼40% of the inhaled dose reaching the systemic circulation. Accumulation was minimal. Twice-daily dosing is supported for future development.
抑制上皮钠通道（ENaC）是一种不依赖于突变的治疗方法，可恢复囊性纤维化患者气道表面液体水合作用和黏液纤毛清除功能。BI 1265162是一种吸入性ENaC抑制剂，已在临床前研究中证明具有疗效。
介绍了BI 1265162在健康男性受试者中的三项I期试验：NCT03349723（单剂量递增试验，评估安全性、耐受性和药代动力学（PK））；NCT03576144（多剂量递增试验，评估安全性、耐受性和PK）；以及NCT03907280（绝对生物利用度试验）。
BI 1265162单剂量≤1200μg和多剂量600μg耐受性良好。各治疗组的不良事件分布均衡，主要为轻度或中度，试验结束时均已缓解。一名受试者在第7天停止试验用药（无症状高钾血症不良事件；第8天恢复）。一名受试者发生严重不良事件（前庭神经病变）并住院治疗，错过了四个给药周期中的一个。这两起事件均被认为与药物无关，受试者均已康复。BI 1265162表现出剂量成比例、与时间无关的药代动力学；最大蓄积倍数为1.6倍；在所测试的剂量范围内，计算得出的有效消除半衰期为3.6 - 8.7小时。肾脏排泄不是主要的药物消除途径。口服和吸入给药（±活性口服炭）的绝对生物利用度分别为0.50%和约40%。
BI 1265162单剂量或多剂量给药长达6.5天耐受性良好。全身暴露主要代表通过肺部而非胃肠道吸收的药物，吸入剂量约40%进入体循环。蓄积作用极小。支持每日两次给药用于未来的研发。
