Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (M.B., C.D.E., J.N.H., E.M.H.); Clinical Pharmacology & Model Stimulation, (E.P., R.W.), Drug Metabolism & Pharmacokinetics, (G.V., D.M., J.M.), Refractory Respiratory Inflammation DPU, (S.U.), In Vitro In Vivo Translation, (C.F.N.), Discovery Medicine, (A.C) GlaxoSmithKline, Stevenage, United Kingdom; Global Clinical Science & Delivery, GlaxoSmithKline, Stockley Park, Uxbridge, United Kingdom (M.M., J.G.); In Vitro In Vivo Translation, (A.H.), Drug Product Design & Development, (M.I.H.), GlaxoSmithKline, Ware, United Kingdom (M.I.H.); Department of Biological Chemistry, Babraham Institute, Cambridge, United Kingdom (J.C.); and Clinical Unit Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom (F.E., D.F.).
Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom (M.B., C.D.E., J.N.H., E.M.H.); Clinical Pharmacology & Model Stimulation, (E.P., R.W.), Drug Metabolism & Pharmacokinetics, (G.V., D.M., J.M.), Refractory Respiratory Inflammation DPU, (S.U.), In Vitro In Vivo Translation, (C.F.N.), Discovery Medicine, (A.C) GlaxoSmithKline, Stevenage, United Kingdom; Global Clinical Science & Delivery, GlaxoSmithKline, Stockley Park, Uxbridge, United Kingdom (M.M., J.G.); In Vitro In Vivo Translation, (A.H.), Drug Product Design & Development, (M.I.H.), GlaxoSmithKline, Ware, United Kingdom (M.I.H.); Department of Biological Chemistry, Babraham Institute, Cambridge, United Kingdom (J.C.); and Clinical Unit Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom (F.E., D.F.)
J Pharmacol Exp Ther. 2019 Jun;369(3):443-453. doi: 10.1124/jpet.119.257311. Epub 2019 Apr 2.
This study describes the pharmacokinetic (PK) and pharmaco-dynamic (PD) profile of -(5-(4-(5-(((2,6)-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (GSK2292767A), a novel low-solubility inhaled phosphoinositide 3-kinase delta (PI3K) inhibitor developed as an alternative to 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (nemiralisib), which is a highly soluble inhaled inhibitor of PI3K with a lung profile consistent with once-daily dosing. GSK2292767A has a similar in vitro cellular profile to nemiralisib and reduces eosinophilia in a murine PD model by 63% ( = 5, < 0.05). To explore whether a low-soluble compound results in effective PI3K inhibition in humans, a first time in human study was conducted with GSK2292767A in healthy volunteers who smoke. GSK2292767A was generally well tolerated, with headache being the most common reported adverse event. PD changes in induced sputum were measured in combination with drug concentrations in plasma from single (0.05-2 mg, = 37), and 14-day repeat (2 mg, = 12) doses of GSK2292767A. Trough bronchoalveolar lavage (BAL) for PK was taken after 14 days of repeat dosing. GSK2292767A displayed a linear increase in plasma exposure with dose, with marginal accumulation after 14 days. Induced sputum showed a 27% (90% confidence interval 15%, 37%) reduction in phosphatidylinositol-trisphosphate (the product of phosphoinositide 3-kinase activation) 3 hours after a single dose. Reduction was not maintained 24 hours after single or repeat dosing. BAL analysis confirmed the presence of GSK2292767A in lung at 24 hours, consistent with the preclinical lung retention profile. Despite good lung retention, target engagement was only present at 3 hours. This exposure-response disconnect is an important observation for future inhaled drug design strategies considering low solubility to drive lung retention.
本研究描述了 -(5-(4-(5-(((2,6)-2,6-二甲基吗啉基)甲基)恶唑-2-基)-1-吲唑-6-基)-2-甲氧基吡啶-3-基)甲磺酰胺（GSK2292767A）的药代动力学（PK）和药效动力学（PD）特征，GSK2292767A 是一种新型低溶解性吸入式磷酸肌醇 3-激酶 δ（PI3K）抑制剂，可作为 2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)恶唑（nemiralisib）的替代物，后者是一种高度可溶性的 PI3K 吸入抑制剂，其肺部特征与每日一次给药一致。GSK2292767A 的体外细胞特征与 nemiralisib 相似，在小鼠 PD 模型中可使嗜酸性粒细胞减少 63%（ = 5， < 0.05）。为了探究低溶解性化合物是否会在人体中产生有效的 PI3K 抑制作用，在健康吸烟者志愿者中进行了一项首次人体研究。GSK2292767A 总体上具有良好的耐受性，最常见的不良反应是头痛。单次（0.05-2mg，n = 37）和 14 天重复（2mg，n = 12）剂量的 GSK2292767A 后，结合血浆药物浓度测量了诱导痰中的 PD 变化。在重复给药 14 天后，进行了支气管肺泡灌洗（BAL）以进行 PK 采样。GSK2292767A 显示出剂量依赖性的血浆暴露线性增加，14 天后略有蓄积。单次给药后 3 小时，诱导痰中的磷脂酰肌醇三磷酸（磷酸肌醇 3-激酶激活的产物）减少了 27%（90%置信区间 15%，37%）。单次或重复给药 24 小时后，减少并未维持。BAL 分析证实，24 小时时 GSK2292767A 仍存在于肺部，与临床前肺部保留特征一致。尽管肺部保留良好，但仅在 3 小时时才存在靶标结合。这种暴露-反应脱节是未来考虑采用低溶解性来提高肺部保留率的吸入药物设计策略的一个重要观察结果。
