Abstract
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.
Highlights
In the treatment of respiratory conditions, targeted drug delivery to its required site of action could provide unique benefits compared to systemic administration
The application of modeling and simulation to characterize the impact of formulation behavior on local and systemic PK following pulmonary administration remains in its infancy
This study has demonstrated an application of BPMX and how it can be a valuable tool to inform drug discovery and development in pulmonary delivery
Summary
In the treatment of respiratory conditions, targeted drug delivery to its required site of action could provide unique benefits compared to systemic administration. Pulmonary delivery of antimicrobial therapies could be beneficial in the treatment of respiratory infections. For these local treatments, the pharmacokinetics (PK) at the site of infection in the lungs is a crucial determinant for drug efficacy. Despite increasing interest in pulmonary drug delivery over the past few decades, the PK of drug molecules following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation to characterize the impact of formulation behavior on local and systemic PK following pulmonary administration remains in its infancy
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