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Background and Objectives <p>Diseases such as cystic fibrosis (CF) and non-CF bronchiectasis can cause extensive mucus formation in the lung, which may affect drug distribution and effects. As such, quantitative understanding of drug distribution in mucus may guide treatment optimization. Here, we aimed to develop a modeling framework to evaluate spatial distribution of drugs in mucus with CF as a proof of concept. In a case study, we demonstrated how spatial PK models can be used to predict spatial antimicrobial pharmacodynamics (PD).</p> Methods <p>A spatial pharmacokinetic (PK) model in mucus was developed using discretized partial differential equations. Hypothetical drugs with realistic ranges for molecule/particle size (radius, <i>r</i>), mucin binding affinity, and half-lives were used to evaluate the impact of drug-specific factors on spatial distribution in mucus. Mucin concentration and muco-ciliary clearance were evaluated as biological system-specific factors. We then demonstrated how the spatial PK model can be used to predict antimicrobial drug effects of imipenem against the pathogen <i>Pseudomonas aeruginosa</i> in mucus.</p> Results <p>Under intravenous PK profiles, molecular/particle size (<i>r</i>) was found to play a dominant role in mucus drug diffusion, while drug-mucin interactions and muco-ciliary clearance showed a minor impact. Small molecule drugs (<i>r</i> &lt;1&#xa0;nm) could readily penetrate mucus, whereas large molecules or particles (<i>r</i> &gt;20&#xa0;nm) showed differential spatial drug distribution. Our case study demonstrates that baseline spatial bacterial organization can impact the treatment outcome of imipenem against mucus-associated infections.</p> Conclusion <p>The developed spatial PK modeling framework enabled quantitative description of the spatial distribution of drugs in airway mucus and can be of relevance to guide optimization of treatment strategies.</p>

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Spatial Pharmacokinetic and Pharmacodynamic Modeling in Airway Mucus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Yuchen Guo,
  • Jinqiu Yin,
  • Sirin Yonucu,
  • Catherijne A. J. Knibbe,
  • Tingjie Guo,
  • J. G. Coen van Hasselt

摘要

Background and Objectives

Diseases such as cystic fibrosis (CF) and non-CF bronchiectasis can cause extensive mucus formation in the lung, which may affect drug distribution and effects. As such, quantitative understanding of drug distribution in mucus may guide treatment optimization. Here, we aimed to develop a modeling framework to evaluate spatial distribution of drugs in mucus with CF as a proof of concept. In a case study, we demonstrated how spatial PK models can be used to predict spatial antimicrobial pharmacodynamics (PD).

Methods

A spatial pharmacokinetic (PK) model in mucus was developed using discretized partial differential equations. Hypothetical drugs with realistic ranges for molecule/particle size (radius, r), mucin binding affinity, and half-lives were used to evaluate the impact of drug-specific factors on spatial distribution in mucus. Mucin concentration and muco-ciliary clearance were evaluated as biological system-specific factors. We then demonstrated how the spatial PK model can be used to predict antimicrobial drug effects of imipenem against the pathogen Pseudomonas aeruginosa in mucus.

Results

Under intravenous PK profiles, molecular/particle size (r) was found to play a dominant role in mucus drug diffusion, while drug-mucin interactions and muco-ciliary clearance showed a minor impact. Small molecule drugs (r <1 nm) could readily penetrate mucus, whereas large molecules or particles (r >20 nm) showed differential spatial drug distribution. Our case study demonstrates that baseline spatial bacterial organization can impact the treatment outcome of imipenem against mucus-associated infections.

Conclusion

The developed spatial PK modeling framework enabled quantitative description of the spatial distribution of drugs in airway mucus and can be of relevance to guide optimization of treatment strategies.