GlaxoSmithKline, Stevenage, United Kingdom.
GlaxoSmithKline, Zeist, the Netherlands.
Clin Ther. 2019 Jun;41(6):1214-1220. doi: 10.1016/j.clinthera.2019.04.008. Epub 2019 May 7.
Nemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate.
In this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic.
APSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC: 17,200 h∙pg/mL; 95% CI, 10,900-27,200 h∙pg/mL and 13,100; 95% CI, 8130-21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses.
After single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.
磷酸肌醇 3-激酶 δ 抑制剂尼拉美利布具有抗炎特性，被研究作为一种免疫调节剂用于慢性阻塞性肺疾病。本研究评估了含有 0.4%硬脂酸镁的尼拉美利布新配方的药代动力学（PK）特性和安全性。
在这项随机、双盲、平行组研究中，健康个体接受了单次剂量的 500 或 750μg 尼拉美利布，通过 Ellipta 干粉吸入器（DPI）给药（每组各 6 人）。在研究前可获得比较新旧配方的空气动力学颗粒大小分布（APSD）数据。在给药后 24 小时内进行了血浆暴露的系列 PK 分析和安全性评估，并在第 3 天和第 6 天在诊所进行了随访测量。
APSD 与之前的（Diskus）配方相比，在极细颗粒质量和细颗粒质量方面增加了约 6 倍和 2 倍。在人体中，吸入 750μg 与 500μg 尼拉美利布后的全身暴露（AUC）更高（AUC：17200h·pg/mL；95%CI，10900-27200h·pg/mL 和 13100；95%CI，8130-21000h·pg/mL）。两种剂量后均报告了个体不良事件的低频率，且无严重不良事件。
在健康个体中单次吸入 Ellipta DPI 的 500 和 750μg 尼拉美利布后，血浆 PK 数据得到了很好的定义，并且根据之前的 PK 和 APSD 数据预测，新配方的暴露量增加。尼拉美利布具有良好的耐受性，未发现新的安全性问题。这些数据支持在慢性阻塞性肺疾病患者中进行尼拉美利布的 IIb 期研究。临床试验注册号：NCT03189589。
