Pharmacokinetic evaluation of inhaled formulations: from in vitro models to clinical assessment

Pulmonary drug delivery systems (PDDS) represent a strategic approach for the localized treatment of respiratory diseases and the systemic administration of biotherapeutics due to their unique physiological advantages. Pharmacokinetic (PK) evaluation serves as the essential link between formulation engineering and clinical efficacy throughout the development and translation of inhaled products. However, current literature often focuses on isolated development stages and lacks a holistic perspective. This review provides a comprehensive overview of PK evaluation methodologies by establishing a systematic framework that integrates in vitro models, in vivo animal studies, clinical assessments, and computational simulations. The discussion covers in vitro and ex vivo systems, including subcellular fractions, cell lines, and emerging organ-on-a-chip technologies for characterizing pulmonary metabolism and transport. It evaluates various animal models, from rodents to non-human primates, for PK screening and dose extrapolation while detailing administration techniques. At the clinical level, the review explains how systemic PK analysis, 3D imaging, and local sampling methods are combined to quantify regional deposition and effective lung exposure. Additionally, the regulatory and translational value of physiologically based pharmacokinetic (PBPK) modeling is highlighted for data integration and bioequivalence assessment. Overall, PK evaluation for inhaled formulations is inherently multidimensional and complex. Future research should prioritize the development of integrated evaluation systems that bridge the gaps between individual models. The integration of artificial intelligence and machine learning is expected to transform aerosol deposition prediction and personalized PBPK modeling, ultimately accelerating the clinical translation of inhaled therapies.