For instance, both dissolved and undissolved drugs will appear in an assay for homogenized lung samples. However, it is practically difficult to separate dissolved drugs in lung samples following administration of a suspension. While slow dissolution of drug particles can provide sustained drug concentrations, only dissolved drugs are available for disposition and activity. For pulmonary suspensions, solubility and dissolution of drug particles in the formulation vehicle are the major determinants of local retention and systemic absorption. It is often impractical to invest heavily in formulation development for a specific compound in this early phase of drug discovery when a wide range of compounds are still being considered. During lead optimization and candidate selection, PK studies are conducted to identify compounds with the best potential for development into a clinical therapy. Consequently, it could be misleading to interpret the PK profiles of drug compounds without taking into account the properties of the formulation used for administration.
However, due to the dissolution of solid drug particles, the absorption of drugs from lung to plasma depends on the properties of the formulation, which affects both local and systemic drug concentrations. While sufficiently soluble compounds can be administered into the lungs as solutions, poorly soluble compounds are commonly administered as a suspension. For pulmonary drug delivery, formulations are dosed into the lungs of the animals. Preclinical studies are invaluable in the lead optimization process in order to evaluate the PK of compounds. (3,6−9) We therefore aim to develop a novel class of anti-virulence agents, quorum-sensing inhibitors (QSIs), for the inhibition of biofilm formation to sensitize PA to antibiotic treatments and attenuate its virulence. To this end, the inhibition of the quorum-sensing (QS) signaling pathway, which regulates the production of multiple virulence factors including traits required for PA biofilm formation and their resistance to antibiotics, has been suggested as a promising target. There have been ongoing efforts to explore new targets on PA infections. (4,5) New treatment options for these infections are therefore of much importance.
(2,3) Previous reports have indicated that about 80% of patients with cystic fibrosis present with chronic PA lung infections. In particular, Pseudomonas aeruginosa (PA), the causative bacterial species in a wide range of pulmonary conditions, has recently developed resistance to many of the current antibiotic therapies available. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.Īntibiotic resistance is a growing challenge and a major public health threat worldwide. 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. 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 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.
NONMEM TUTORIAL SERIES
The observed drug concentration–time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. 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. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration.
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