Inhalation is the primary route of administration for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), because it delivers drugs directly to the lung while reducing systemic exposure. Unlike oral or injectable drugs, inhaled therapies are designed mainly for local pulmonary action, so pharmacokinetic assessment should focus on lung exposure rather than only plasma concentrations. Traditional PK studies based primarily on systemic drug levels may underestimate local efficacy and overlook pulmonary toxicity risks. Therefore, inhaled drug development requires a pulmonary-centric PK framework that directly evaluates drug deposition, residence time, distribution, absorption, and clearance within the respiratory tract.
Pulmonary delivery depends on multiple formulation, physiological, and physicochemical factors. Inhaled drugs are usually delivered as aerosols or dry powders that deposit in the trachea, bronchioles, or alveoli depending on particle size, inhalation flow, and airway anatomy. Particles with an aerodynamic diameter below 5 μm are generally more suitable for reaching the lower airways and alveoli. Drug solubility, lipophilicity, aerosolization properties, and epithelial permeability also influence how efficiently the drug reaches target cells. After deposition, inhaled drugs must dissolve in lung lining fluid, cross the epithelial barrier, and avoid or undergo local clearance mechanisms such as macrophage phagocytosis, mucociliary transport, lymphatic drainage, and absorption into pulmonary capillaries. These processes determine local drug exposure and may not be accurately reflected by plasma PK data.
Because plasma concentrations represent only the fraction of inhaled drug that enters systemic circulation, they provide limited information about pulmonary drug disposition. Lung tissue and epithelial lining fluid concentrations can be much higher than plasma levels, especially shortly after dosing, and local lung metabolism or rapid pulmonary clearance may further weaken the relationship between systemic exposure and local effect. To address these limitations, alternative pulmonary PK methods are increasingly used. Lung tissue sampling can quantify regional drug distribution and retention, while bronchoalveolar lavage fluid analysis provides information on the pulmonary lining environment and inflammatory markers. PET and SPECT imaging allow non-invasive visualization of lung distribution, and pulmonary microdialysis can measure unbound drug concentrations in lung tissue over time. Each method has limitations, so pulmonary PK assessment often requires combining multiple approaches.
Animal models are indispensable for preclinical pulmonary PK studies, but their translational value varies by species. Rodents are useful for early screening, mechanistic research, and formulation development, but differences in airway structure, respiratory rate, and deposition patterns limit direct translation to humans. Guinea pigs, hamsters, dogs, and rabbits can support airway reactivity, inflammation, lung function, or inhalation toxicology studies, but they still differ from humans in key anatomical and physiological features. Non-human primates, such as cynomolgus and rhesus macaques, provide the highest translational relevance because their lung anatomy, airway branching, respiratory physiology, mucociliary clearance, and immune responses are closer to humans. Although NHP studies are costly and require specialized ethical and operational controls, they are particularly valuable for complex inhaled formulations, long-term delivery studies, inhalation toxicology, pulmonary tissue retention, local efficacy, and toxicity assessment.
Successful clinical translation of inhaled drugs requires integrating pulmonary PK data from animal models, especially NHPs, with PK/PD relationships, toxicity endpoints, PBPK modeling, and limited clinical sampling or imaging when feasible. Since direct measurement of human lung drug concentrations is technically and ethically difficult, tools such as PET or SPECT imaging, BALF or sputum sampling, and physiologically based modeling can help bridge preclinical and clinical data. Future inhaled drug development should establish standardized pulmonary PK endpoints, such as lung tissue AUC, BALF concentrations, and lung residence time; improve non-invasive and quantitative lung exposure technologies; optimize formulation and device development using relevant large animal models; and link pulmonary exposure directly with efficacy and toxicity outcomes. Overall, inhaled drug development is shifting from a systemic exposure-based paradigm toward a pulmonary local exposure-based framework.
