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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Translation of Inhaled Drug Optimization Strategies into Clinical Pharmacokinetics and Pharmacodynamics Using GSK2292767A, a Novel Inhaled Phosphoinositide 3-Kinase delta Inhibitor
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Translation of Inhaled Drug Optimization Strategies into Clinical Pharmacokinetics and Pharmacodynamics Using GSK2292767A, a Novel Inhaled Phosphoinositide 3-Kinase delta Inhibitor

机译：用GSK2292767A将吸入药物优化策略的吸入药物优化策略，一种新型吸入磷酸阳性3-激酶Delta抑制剂的临床药代动力学和药效学

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摘要

This study describes the pharmacokinetic (PK) and pharmacodynamic (PD) profile of N-(5-(4-(5-(((2R, 6S)-2,6-dimethylmorpholino)methyl) oxazol-2-yl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (GSK2292767A), a novel low-solubility inhaled phosphoinositide 3-kinase delta (PI3K delta) inhibitor developed as an alternative to 2-(6-(1H-indol-4-yl)-1H-indazol4-yl)-5-((4-isopropylpiperazin-1-yl) methyl) oxazole (nemiralisib), which is a highly soluble inhaled inhibitor of PI3K delta 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% (n = 5, P < 0.05). To explore whether a low-soluble compound results in effective PI3Kd 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 themost common reported adverse event. PDchanges in induced sputum were measured in combination with drug concentrations in plasma from single (0.05-2 mg, n = 37), and 14-day repeat (2 mg, n = 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.
机译：本研究描述了N-（5-（（（（（2R，6S）-2,6-二甲基丙酮基）甲基）的药代动力学（PK）和药物动力学（PD）分布）恶唑-2-基）-1h -indazol-6-yl）-2-甲氧基吡啶-3-基）甲磺酰胺（GSK2292767A），一种新型低溶解度吸入磷酸膦酸3-激酶δ（PI3K DELTA）抑制剂，作为2-（6-（1H-）的替代方案吲哚-4-基）-1H-Indazol4-Y1）-5 - （（4-异丙基哌嗪-1-基）甲基）恶唑（Nemiralisib），其是PI3Kδ的高度可溶性吸入抑制剂，其肺部曲线一致-daily给药。 GSK2292767A具有与Nemiralisib的体外细胞谱不同的体外细胞谱，并在鼠PD模型中减少63％（n = 5，P <0.05）中的嗜酸性粒细胞症。为了探索低可溶性化合物是否导致人类中有效的PI3KD抑制，在冒烟的健康志愿者中首次进行人类研究。患有GSK2292767A。 GSK2292767A通常耐受良好，头痛是普通普通报告的不良事件。诱导痰中的PDCHANGES与来自单个（0.05-2mg，n = 37）的血浆中的药物浓度组合测量，14天重复（2mg，n = 12）GSK2292767A。在重复剂量的14天后服用PK的Trough Bronchoalveolar灌洗液（BAL）。 GSK2292767A显示用剂量的血浆暴露的线性增加，14天后具有边缘累积。诱导痰显示出磷脂酰肌醇三磷酸三种磷酸三种磷酸三种磷酸三种磷酸三种磷酸（磷酸膦酸阳性3-激活的产物）的27％（90％置信区间，37％）。单身或重复给药后2小时不需要减少。 BAL分析在24小时内确认了GSK2292767A在肺中的存在，与临床前肺保留曲线一致。尽管肺部保留良好，但目标订婚仅在3个小时内出现。这种曝光 - 反应断开连接是考虑低溶解度以驱动肺保留的未来吸入药物设计策略的重要观察。

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