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

Abstract

For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration–time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Simulations of lipid bilayers containing products of lipid oxidations have found a decrease in permeability for the case of oxysterols [550] and tail oxidized phosphatidylcholine [481]. From the standpoint of pharmaceutical research, the most interesting are studies of membranes that form a boundary with an extracellular environment, including bacterial membranes [415,[610][611][612][613][614][615][616], the stratum corneum, i.e., the most external layer of the skin [617][618][619][620][621][622][623][624][625][626], membranes present in the eyes [557,[627][628][629][630][631], and the ocular mucous membrane [632], or lung surfactant monolayers [263,558,[633][634][635][636][637][638]. Specifically, MD simulations have been used in studies of enhancer effects on the permeability of the stratum corneum (e.g., [544]).…”

Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections

“…The hepatic stability of 6f was investigated in our previous report; 42 6f performed inadequately in hepatic stability testing when exposed to human and rat microsomes where the 6f half-life was determined to be relatively short. These results were further corroborated in a PK profiling study of 6f following intratracheal administration in rats as a coarse suspension.…”

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials

“…More extensively, the application of biopharmaceutical pharmacometrics (BPMX)-i.e., pharmacometric modeling incorporating biopharmaceutical principles has been demonstrated as a valuable tool in drug discovery and development. For instance, Sou et al [59] reported the application of BPMX for the PK analysis of three investigational antimicrobial agents following pulmonary administration of different suspension formulations. They developed a PK model considering formulation properties and provided a mechanism to estimate dissolved drug concentrations in the lungs.…”