Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions.
Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions.
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肺给药中的模型知情药物发现和开发：用于肺混悬液配方评估的生物制药药物计量模型。
DOI：
10.1021/acsomega.0c03004
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发表时间：
2020-10-13
期刊：
影响因子：
4.1
通讯作者：
Bergström CAS
中科院分区：
文献类型：
--
作者：
Sou T;Soukarieh F;Williams P;Stocks MJ;Cámara M;Bergström CAS
对于呼吸系统疾病，与全身给药相比，靶向肺部给药可产生更高的局部浓度，同时降低不良事件的风险。尽管对肺部给药的兴趣越来越大，但肺部给药后药物的药代动力学（PK）仍有待阐明。在这种情况下，应用建模和模拟方法来表征肺部给药后化合物的PK特性仍然是稀缺的。铜绿假单胞菌（PA）肺部感染对目前的许多抗生素治疗具有耐药性。肺部递送的靶向治疗可能对这些局部病症特别有益。在这项研究中，我们报告了应用生物制药药物计量学（BPMX）的PK数据分析从三个研究抗菌药物肺部给药后的悬浮液配方。将观察到的化合物系列的肺和血浆中的药物浓度-时间曲线合并用于同时分析和建模。所开发的模型描述了PK数据，考虑到制剂特性，并提供了一种预测肺中可用于活性的溶解药物浓度的机制。然后使用该模型评价制剂效应以及变异性对肺和血浆中总药物浓度和溶解药物浓度的影响。这些预测表明，这些用于肺部递送的疗法理想地应该以具有高溶解度的缓释制剂递送，以在肺中最大局部暴露以获得功效，在血浆中快速全身清除以降低不希望的全身不良反应的风险。这项工作显示了BPMX的潜在好处，以及它在肺部给药中支持药物发现和开发的作用。
For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration–time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.
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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
影响因子：
3.7
作者：
Andersson, Sara B. E.;Alvebratt, Caroline;Bergstrom, Christel A. S.
通讯作者：
Bergstrom, Christel A. S.
影响因子：
6.1
作者：
Lindbom, L;Ribbing, J;Jonsson, EN
通讯作者：
Jonsson, EN
影响因子：
4.9
作者：
Eriksson, Johanna;Thorn, Helena;Lennernas, Hans
通讯作者：
Lennernas, Hans
影响因子：
5.2
作者：
Mouton, JW;Dudley, MN;Drusano, GL
通讯作者：
Drusano, GL