Development and evaluation of a PBPK model to study the pharmacokinetics of inhaled drugs in rats
Silvia Grandoni (1), Nicola Cesari (2), Nicola Melillo (1), Giandomenico Brogin (2), Paola Puccini (2), Paolo Magni (1)
(1) Università degli Studi di Pavia, Dept. Electrical, Computer and Biomedical Engineering, Pavia, Italy, (2) Chiesi Farmaceutici S.p.A, Pharmacokinetic, Biochemistry and Metabolism Department, Parma, Italy.
Objectives: development and evaluation of a PBPK model to study the pharmacokinetics of inhaled drugs in rats, using test compounds with different solubility and permeability characteristics.
Methods: a physiologically-based pulmonary model was integrated in a previously developed in house WB-PBPK model [1], with the aim of simulating intratracheal (IT) administrations in rats. The pulmonary model structure reflects the division of the respiratory system in a central and peripheral region, as previously proposed in [2] and [3] and each region is characterized by a different volume, surface and perfusion (the first region is connected with the systemic circulation, the second one with the pulmonary circulation). In each region the drug deposits, following a certain deposition pattern, in its undissolved form, then it can dissolve in the lung fluid and be absorbed through the tissue. The mucociliary clearance process is added as acting on the undissolved drug in the central region. Lung tissue is modelled as a permeability limited tissue as proposed in [4], a bidirectional transport is considered, so that there is a drug exchange between lung tissue and fluids (i.e., the epithelial lining fluid and blood) via passive transport. An additional monodirectional transport is also included in the model to take into account the possible action of the efflux transporters such as the P-glyco proteins. The quantification of the lung tissue permeability was done through a simple modelling of the in vitro Calu3 permeability test data. This model is composed by three compartments: the apical media, the cells and the basolateral media. It is assumed that the main fluxes in the system are due to the passive bidirectional transport between lung cells and the two fluids and to the monodirectional efflux from the tissue to the epithelial lining fluid; furthermore, the drug binding to the Calu3 cells is included. The model was tested using in-house plasma and lung concentration data obtained after IT administration in rats. We started from compounds with high pulmonary solubility, for which the permeation through the lung tissue is the absorption rate limiting step with the aim of testing the permeability model, after that, the model was tested considering compounds with low solubility to test the whole model.
Results: the model was evaluated by using experimental data obtained after IT administration of 9 different compounds, through a visual comparison between the simulated profiles and the experimental data and a quantitative comparison between the Area Under the Curve (AUC), the maximum concentration (Cmax) and the Mean Residence Time (MRT) computed on the simulated plasma and lung concentration profiles and on the collected data. The first comparison, focused on the highly soluble compounds, showed that the model is able to correctly predict the time course of the plasma and lung concentration, both in terms of profile shape and of PK parameters. Average fold errors related to plasma and lung were computed and are close to 1. Similar results were found for poorly soluble compounds.
Conclusions: the results obtained suggest that the model is able to describe the plasma and lung concentration-time profiles in the preclinical species rat and can be considered as a base for translational purposes.
References:
[1] Grandoni et al., “Building in-house PBPK modelling tools for oral drug administration from literature information”, ADMET & DMPK, 7 (1), 2019.
[2] Caniga et. al., “Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions”, Journal of aerosol medicine and pulmonary drug delivery, 29 (4), 2016.
[3] Boger et. al., “Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs”, CPT: Pharmacometrics & Systems Pharmacology, 5 (4), 2016.
[4] Gaohua et al., “Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs”, CPT: Pharmacometrics & Systems Pharmacology, 4 (10), 2015.