Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection.
Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection.
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基于模型的肺部给药药物开发：治疗铜绿假单胞菌肺部感染的新候选药物的药代动力学分析。
DOI：
10.1016/j.xphs.2018.09.017
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发表时间：
2019-01
影响因子：
3.8
通讯作者：
Bergström CAS
中科院分区：
文献类型：
--
作者：
Sou T;Kukavica-Ibrulj I;Soukarieh F;Halliday N;Levesque RC;Williams P;Stocks M;Cámara M;Friberg LE;Bergström CAS
抗生素耐药性是全球范围内的一大公共卫生威胁。尤其是，约80%的囊性纤维化患者患有慢性铜绿假单胞菌(PA)肺部感染，对目前的许多抗生素耐药。因此，我们正在开发一类新型的抗病毒药物--群体感应抑制剂(QSIS)，它可以抑制生物被膜的形成，并使PA对抗生素治疗敏感。对于呼吸系统疾病，靶向肺部给药可以实现更高的局部浓度，并降低不良全身事件的风险。在这项研究中，我们报道了三种QSIS原型在肺部给药后的药代动力学，并用药物计量学模型方法同时分析了支气管肺泡灌洗、肺组织匀浆和血浆样品的药物浓度-时间曲线。除了便于直接比较和选择候选药物外，开发的模型还用于剂量模拟研究，以预测在不同剂量情况下体内暴露的情况。结果表明，全身清除对肺部给药后局部药物暴露的影响有限。因此，我们建议，设计用于肺部给药的新型QSIS作为呼吸道疾病的靶向治疗，理想情况下应该在肺内具有较长的停留时间，以实现局部疗效，并在全身吸收后迅速清除，以降低全身不良事件的风险。
Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.
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预测吸入支气管扩张剂对人体肺部药代动力学和疗效的转化模型。
DOI：
10.1002/psp4.12270
发表时间：
2018-03
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Hendrickx R;Lamm Bergström E;Janzén DLI;Fridén M;Eriksson U;Grime K;Ferguson D
通讯作者：
Ferguson D
影响因子：
6.7
作者：
Ilangovan A;Fletcher M;Rampioni G;Pustelny C;Rumbaugh K;Heeb S;Cámara M;Truman A;Chhabra SR;Emsley J;Williams P
通讯作者：
Williams P
DOI：
10.1007/s10928-015-9438-9
发表时间：
2015-12-01
影响因子：
2.5
作者：
Clewe, Oskar;Karlsson, Mats O.;Simonsson, Ulrika S. H.
通讯作者：
Simonsson, Ulrika S. H.
DOI：
10.1016/j.ddtec.2014.02.003
发表时间：
2014-03-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Jolivet-Gougeon, Anne;Bonnaure-Mallet, Martine
通讯作者：
Bonnaure-Mallet, Martine
影响因子：
1.9
作者：
Padden, Jennifer;Skoner, David;Hochhaus, Gunther
通讯作者：
Hochhaus, Gunther