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Background and purpose Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration. Experimental approach Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol, and fluticasone propionate (n=12), or oral salbutamol and propranolol (n=6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two time points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 hours). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy, and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 hours after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings. Key results Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue, and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung versus plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable, whereas, for oral drugs, epithelial-lining-fluid concentrations appeared to be overestimated in bronchoalveolar-lavage-generated profiles. Conclusion and implications Combining pharmacokinetic data derived from multiple individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.

After inhaled drug administration, pharmacokinetic (PK) data is typically limited to plasma concentrations and provides no direct information on lung target site levels. This study aims to increase understanding of regional lung PK of selected drugs by taking samples from various lung compartments using innovative sampling methods. Eighteen healthy volunteers were enrolled to either receive single doses of orally inhaled salbutamol (200µg), salmeterol (50µg) and fluticasone propionate (500µg) (n=12) or single oral doses of salbutamol (4 mg) and propranolol (40 mg) (n=6). Two bronchoscopies were performed in each subject. During each bronchoscopy 2 samples of bronchosorption, bronchial brush, mucosal biopsy and one bronchoalveolar lavage (BAL) were performed at different pre-specified times (1, 2, 3, 4, 6, 9, 12, 18 hours) after the drug administration. PK profiles of the model drugs were obtained for concentrations in human lung epithelial lining fluid and lung tissue, enabling insight into the spatial lung distribution of drugs after inhaled and oral administration (Fig. 1). Innovative study design with direct sampling from different compartments in lung provided high quality PK profiles in human lung and demonstrated extent of lung targeting following inhaled drug delivery.