Introduction:

This contribution contains the MoBi implementation of a mechanistic physiologically-based pharmacokinetic inhalation model that brings together lung anatomy, particle deposition, particle dissolution, and mucociliary clearance from previous work and connects it to a two-compartment model.

In this model, the lung is separated into the extrathoracic region and 24 lung generations (or sections) that each consist of concentric layers: epithelial lining fluid, epithelium, and subepithelium. The model allows for absorption of particles in the lung as well as oral absorption of particles in the extrathoracic region.

Using MoBi and the ospsuite R package, the user enters parameters describing the physicochemical properties of the molecule, the micro-constants pertaining to the two-compartment model, oral and lung bioavailabilities, particle size distribution, and dose.

Simulation of the model returns:

• amount or concentration of drug at each compartment and at each generation of the lung over the time of the simulation,
• amount or concentration of drug at each compartment of the two-compartment model as well as the extrathoracic region.

This repository is organized as follows:

File name	Description
Inhalation_model_user_guide.pdf	Includes: 1. Introduction to the model and model details 2. A description of the model implementation in Mobi 3. Step-by-step tutorial of a basic inhalation simulation
Inhalation_model_structure_evaluation.pdf	Slide deck demonstrating the use of the inhalation model to capture the observed behaviour of four molecules of varying solubilities.
inhalation_model_two_compt_1_bin.mbp3	MoBi project template containing the inhalation model connected to a two-compartment model
populate_model.R	R script that is used to calculate deposition fractions based on empirical equations (Yu & Diu, 1982)
custom_deposition.R	R script that is used to specify the deposition fractions directly
configure_inhalation_parameters.R	Template to guide the use of the populate_model.R and custom_deposition.R files. It is currently configured for the ciprofloxacin which is used in the tutorial within the user guide
ParticleBin_1.pkml	Template for a single particle bin. This file can be used to add additional particle bins in the case of a polydisperse formulation
Standard_Molecule.pkml	Template for a generic molecule building block. This file is used to load the parameter "Solubility in epithelial lining fluid"
stass_2017_ciprofloxacin_inhaled.pkml	Building block that contains Stass et al (2017) data used in the tutorial within the user guide

References

[1] Boger, E., & Fridén, M. (2019). Physiologically based pharmacokinetic/pharmacodynamic modeling accurately predicts the better bronchodilatory effect of inhaled versus oral salbutamol dosage forms. Journal of aerosol medicine and pulmonary drug delivery, 32(1), 1-12.

[2] Boger, E., & Wigström, O. (2018). A partial differential equation approach to inhalation physiologically based pharmacokinetic modeling. CPT: pharmacometrics & systems pharmacology, 7(10), 638-646.

[3] Stass, H., Nagelschmitz, J., Kappeler, D., Sommerer, K., Kietzig, C., & Weimann, B. (2017). Ciprofloxacin dry powder for inhalation in patients with non-cystic fibrosis bronchiectasis or chronic obstructive pulmonary disease, and in healthy volunteers. Journal of aerosol medicine and pulmonary drug delivery, 30(1), 53-63.

[4] Weibel, E. R., Cournand, A. F., & Richards, D. W. (1963). Morphometry of the human lung (Vol. 1). Berlin: Springer.

[5] Willmann, S., Thelen, K., Becker, C., Dressman, J. B., & Lippert, J. (2010). Mechanism-based prediction of particle size-dependent dissolution and absorption: cilostazol pharmacokinetics in dogs. European journal of pharmaceutics and biopharmaceutics, 76(1), 83-94.

[6] Yu, C. P., & Diu, C. K. (1982). A comparative study of aerosol deposition in different lung models. American Industrial Hygiene Association Journal, 43(1), 54-65.