A Subcellular Compartmental Modeling Approach to Pulmonary Drug Development.

Abstract

Predicting and controlling the systemic and local pharmacokinetics of pulmonary medications in different regions of the lung is critical for optimizing the efficacy and safety of inhaled drugs. Here, a modular, multiscale, physiologically-based pharmacokinetic (1Cell PBPK) model of the lung was developed to simulate the time-course concentration of inhaled and systemically-injected compounds. The model captured the transport and distribution of drug in airways and alveoli, from the subcellular level to the whole organ level. Mathematically Fick’s law and the Nernst-Plank equation were used to capture the mass transport of lipophilic drug molecules across cellular membranes. Henderson-Hasselbalch equation was used to capture the different ionization states of a molecule at a given pH. The fundamental transport properties of monobasic compounds across a series of cellular compartments were described by sets of coupled ordinary differential equations (ODEs). The physicochemical properties of the compounds (i.e., pKa and logP) were used as input parameters. Anatomical and physiological input parameters were incorporated to model the structure and function of the lung, including the extracellular and intracellular pH values, lipid composition, cell thickness, membrane areas, cell volume, and membrane potential of the various different cell types that form the airways and alveoli. Values of input parameters were varied to capture the uncertainty associated with normal and pathological conditions. For the purpose of model validation, the predicted PK profiles of compounds in lungs were compared to experimentally measured data. Lastly, to advance practical applications, the model was used as a starting point for developing a rational approach to optimize the pharmaceutical properties of inhaled drug formulations, based on their dissolution and absorption properties. In this manner, cell-based multiscale mathematical simulations of pharmacokinetics can overcome limitations associated with existing preclinical models used in pulmonary drug development, providing a rational basis for medicinal chemists and pharmaceutical scientists to guide the design of inhaled medications for lung and systemic diseases.PhDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/86542/1/yujy_1.pd