Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection

Abstract

Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.

Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions

“…Previous analogues of the compounds have been shown to be rapidly absorbed when given as a solution formulation. 11 The results in the present study showed that these compound analogues were easily absorbed even when given as a suspension formulation. Such rapid absorption has also been reported with other antimicrobial agents.…”

“…The relatively simple formulation vehicle used in this study was established previously to improve solubility of the compound series with excipients that have been shown to be suitable for lung administration. 11 , 20 − 22 …”

“…It was expected that the excipients in the formulation vehicle would increase the solubility of the compound series as previously shown with the analogues. 11 However, despite the use of the formulation medium, only 5 to 21% of the compounds were dissolved when prepared at a concentration of 0.5 mg/mL. The compounds were therefore given as a suspension formulation into the lungs of the animals.…”

“…When the drug was completely dissolved in the formulation (i.e., F d = 1), the concentrations in both lung and plasma declined much more rapidly than the ones resulting from suspension formulations and decreased by more than 3 orders of magnitude within 2 h. This was consistent with the rapid absorption and clearance observed when the analogues of the compound series were administered as solution formulations to the lungs. 11 Without the sustained release properties resulting from the slow dissolution of drug particles, drugs in solution were rapidly absorbed and cleared systemically. The high metabolism, as suggested by the results from the rat liver microsome study, likely also contributed to the rapid systemic clearance.…”

“…They are, however, structural analogues of SEN001 as shown previously. 11 Polyethylene 400 (PEG400) and polysorbate 80 (PS80) were purchased from Sigma-Aldrich (Stockholm, Sweden).…”