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Combined in Vitro-in Silico Approach to Predict Deposition and Pharmacokinetics of Budesonide Dry Powder Inhalers
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2020-09-29 , DOI: 10.1007/s11095-020-02924-7
Conor A Ruzycki 1 , Brynn Murphy 1 , Hafeez Nathoo 1 , Warren H Finlay 1 , Andrew R Martin 1
Affiliation  

Purpose

A combined in vitro – in silico methodology was designed to estimate pharmacokinetics of budesonide delivered via dry powder inhaler.

Methods

Particle size distributions from three budesonide DPIs, measured with a Next Generation Impactor and Alberta Idealized Throat, were input into a lung deposition model to predict regional deposition. Subsequent systemic exposure was estimated using a pharmacokinetic model that incorporated Nernst-Brunner dissolution in the conducting airways to predict the net influence of dissolution, mucociliary clearance, and absorption.

Results

DPIs demonstrated significant in vitro differences in deposition, resulting in large differences in simulated regional deposition in the central conducting airways and the alveolar region. Similar but low deposition in the small conducting airways was observed with each DPI. Pharmacokinetic predictions showed good agreement with in vivo data from the literature. Peak systemic concentration was tied primarily to the alveolar dose, while the area under the curve was more dependent on the total lung dose. Tracheobronchial deposition was poorly correlated with pharmacokinetic data.

Conclusions

Combination of realistic in vitro experiments, lung deposition modeling, and pharmacokinetic modeling was shown to provide reasonable estimation of in vivo systemic exposure from DPIs. Such combined approaches are useful in the development of orally inhaled drug products.



中文翻译:

结合体外计算机模拟方法预测布地奈德干粉吸入器的沉积和药代动力学

目的

设计了一种体外-计算机模拟相结合的方法,以评估通过干粉吸入器递送的布地奈德的药代动力学。

方法

用新一代Impactor和Alberta Idealized Throat测量的三个布地奈德DPI的粒径分布被输入到肺部沉积模型中,以预测区域沉积。随后的全身暴露使用药代动力学模型进行估算,该模型将Nernst-Brunner溶出度合并在导气管中,以预测溶出度,粘膜纤毛清除和吸收的净影响。

结果

DPIs在体外显示出明显的沉积差异,导致中央传导气道和肺泡区域的模拟区域沉积差异很大。每个DPI都在小型导气管中观察到类似但很低的沉积。药代动力学预测与文献中的体内数据显示出良好的一致性。峰值全身浓度主要与肺泡剂量有关,而曲线下的面积更多地取决于总肺剂量。气管支气管沉积与药代动力学数据相关性很差。

结论

结合实际的体外实验,肺部沉积模型和药代动力学模型,可以合理估计DPI在体内的全身暴露。这样的组合方法可用于口服药物产品的开发。

更新日期:2020-09-30
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