Predicting systemic and pulmonary tissue barrier concentration of orally inhaled drug products

Abstract

The complex physiology and anatomy of the lungs and the range of processes involved in pulmonary drug transport and disposition make it challenging to predict the fate of orally inhaled drugs. This study aimed to develop an integrated computational pharmacology approach to mechanistically describe the spatio-temporal dynamics of inhaled drugs in both systemic circulation and site-specific lung tissue. The model included all the physiologically relevant pulmonary processes, such as deposition, dissolution, transport across lung barriers, and mucociliary clearance, to predict the inhaled drug pharmacokinetics. For validation test cases, the model predicted the fate of orally inhaled budesonide (highly soluble, mildly lipophilic) and fluticasone propionate (practically insoluble, highly lipophilic) in healthy subjects for: i) systemic and site-specific lung retention profiles, ii) aerodynamic particle size-dependent deposition profiles, and iii) identified the most impactful drug-specific, formulation-specific, and system-specific property factors that impact the fate of both the pulmonary and systemic concentration of the drugs. In summary, the presented multiscale computational model can guide the design of orally inhaled drug products to target specific lung areas, identify the effects of product differences on lung and systemic pharmacokinetics, and be used to better understand bioequivalence of generic orally inhaled drug products. Author summaryDespite widespread use of available orally inhaled drug products (OIDPs), much is unknown regarding their optimal lung deposition, targeted delivery to specific lung regions, and the effects of various device, formulation, and physiological factors on deposition, absorption, transport, and clearance. In this study, we have presented a multiscale computational framework that integrates a full-scale 24 generation 3D lung model with distinct barrier regions spanning trachea, tracheobronchial, alveolar, and the terminal alveolar sacs with multiple other modules to track the OIDP levels (concentration) in both blood and pulmonary tissue regions. Along with validating the framework on two different inhaled drug types, we have also presented a sensitivity analysis to highlight the most impactful drug and formulation parameters, and therefore, potential optimization parameters to modulate lung selectivity and to better understand the pulmonary retention of drugs in distinct lung regions.