Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs

Abstract

Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug‐ and formulation‐specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose‐only inhalation. As the model clearly distinguishes among drug‐specific, formulation‐specific, and system‐specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug‐receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.

A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

“…In contrast, this could not be demonstrated earlier by a two‐compartment inhalation PBPK model 9. This shows that conclusions from a lumped region are not necessarily valid across the entire space.…”

“…and the heterogeneous nature of the organ and particle distribution should be taken into account. Currently, there exist several different inhalation physiologically based pharmacokinetic (PBPK) models, each of which covers some but not all of these important phenomena 9, 10, 11, 12, 13…”

“…9, 14. To describe the interaction between the lungs and the systemic circulation, it is important to allow for a back‐flow of drug from the blood to the lungs.…”

“…In addition, the radius shrinkage rate of dissolving particles is singular as the particle radius tends to zero. Current models avoid numerical issues by compromising mass balance and adding computational burden 9, 13…”

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

“…Also, the influence of target expression and target accesibility on target saturation and its duration has been described in quantitative terms before (64). Moreover, the relevance of the k off for transient tissue selectivity has been demonstrated before in a PBPK model for inhaled drugs (65). For the development of more selective drugs, target concentrations of both the intended target and off-targets as well as distribution to the target tissue/target site should be taken into consideration.…”