Abstract
The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against data from different clinical studies. Without adapting the mechanistic model or estimating kinetic parameters based on individual study data, the developed model was able to predict simultaneously (i) lung retention profiles of inhaled insoluble particles, (ii) particle size-dependent pharmacokinetics of inhaled monodisperse particles, (iii) pharmacokinetic differences between inhaled fluticasone propionate and budesonide, as well as (iv) pharmacokinetic differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, the developed mechanistic model was applied to investigate the impact of input parameters on both the pulmonary and systemic exposure. Interestingly, the solubility of the inhaled drug did not have any relevant impact on the local and systemic pharmacokinetics. Instead, the pulmonary dissolution rate, the particle size, the tissue affinity, and the systemic clearance were the most impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool for identifying optimal drug and formulation characteristics.
Highlights
Oral drug inhalation can result in high pulmonary drug exposure while maintaining low systemic exposure
The use of orally inhaled drugs for treating lung diseases is appealing since they have the potential for lung selectivity, i.e. high exposure at the site of action –the lung– without excessive side effects
The degree of lung selectivity depends on a large number of factors, including physiochemical properties of drug molecules, patient disease state, and inhalation devices
Summary
Oral drug inhalation can result in high pulmonary drug exposure while maintaining low systemic exposure. The pharmacodynamic (PD) selectivity for the lung was previously investigated, a sound quantitative understanding about the pulmonary pharmacokinetics (PK) is still lacking. Specific pulmonary PK processes after oral drug inhalation were studied in detail, such as the pulmonary particle deposition [6,7,8] or mucociliary clearance [9, 10]. A comprehensive quantitative understanding of how these processes contribute to pulmonary and systemic PK, and to lung selectivity after drug inhalation, is often still lacking [11,12,13,14]. Identifying drug and formulation characteristics for orally inhaled drugs that maximize lung selectivity as well as long-lasting pulmonary efficacy is still challenging
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