Silvia Grandoni1, Nicola Cesari1, Maria Rosaria Di Lascia1, Alessandro Fioni1, Giandomenico Brogin1, Paola Puccini1
1Chiesi Farmaceutici S.p.A.
Objectives: the evaluation of the target site exposure is essential for a better understanding of the PK-PD relationships of locally acting inhaled drugs. PBPK models are powerful tools in this context as their structure allow separation between drug- and system-specific properties, giving insights in which drug and/or formulation-specific properties modulate lung exposure leading to favorable PK-PD-safety profiles [1]. In addition, the parametrization based on physiology facilitates the translation updating the model with human system-specific properties [1]. In this work, a translational PBPK modelling framework to support the preclinical to clinical translation of inhaled compounds is presented. It was built to predict the human PK leveraging data routinely collected during the preclinical development such as in vitro pulmonary ADME data, formulation data, and in vivo lung PK in rodents. The ability of the model to describe lung and plasma PK in rats after intratracheal (IT) administration, the starting point for translation, was evaluated for several compounds. The model performances in extrapolating the human PK after inhalation were evaluated focusing on plasma PK of highly soluble compounds with negligible oral bioavailability or co-administered with charcoal, to have insights on the ability to describe the pulmonary absorption process [2]. Methods: the PBPK model consists of a whole-body structure including a gastrointestinal absorption model [3]. A pulmonary model is integrated to describe the PK of inhaled compounds [4]. The lung is modelled as two regions representing the tracheobronchial and the respiratory region. The main processes governing the pulmonary PK i.e. deposition, dissolution, mucociliary clearance and absorption are modelled. The corresponding equations are formulated to incorporate formulation and compound properties such as the powder particle size distribution (PSD), solubility in simulated lung fluid and binding to it, and lung tissue binding. The translational workflow consists of different steps. Initially, rat lung and plasma PK data after IT administration are modelled. At this stage, the effective pulmonary permeability is calibrated on in vivo PK starting from in vitro Caco2 cell data. The regional deposition is computed with the MPPD tool [5], for rats it is based on the PSD and on the characteristics of the IT administration device. Subsequently, for the translational step, species-specific parameters were updated with the human ones, lung drug-specific parameters were kept fixed from the previous step. The regional deposition in humans was computed based on the characteristics of the inhalation device and the PSD of the formulation. The model was developed in MATLAB. Model performances were evaluated via visual inspection of the predicted profiles against in vivo data and comparison of the PK metrics AUC, Cmax and MRT obtained from in vivo data with those computed on simulated profiles. Results: the model was able to describe plasma and lung PK profiles in rats after IT administration. The human plasma PK after inhalation was successfully predicted leveraging in vitro compound and formulation data, and calibration on preclinical PK data. With a few exceptions, for all the compounds, all the computed metrics were within the 2-fold error. In addition, during the model calibration step on in vivo rat lung PK data a correlation between the pulmonary effective and the in vitro Caco2 permeability was found. Conclusions: a translational framework incorporating the key processes driving the lung PK was built to support the extrapolation of the PK of orally inhaled compounds in humans. The performances in the preclinical species support its use for the evaluation of the PK-PD relationship in animals. These encouraging results related to the human PK extrapolation support further investigations with poorly soluble compounds for its use to guide the design of first time in human trials. In addition, the correlation obtained to calculate the effective permeability could be potentially used for the prediction of human lung PK of new compounds at early stages directly from in vitro data, guiding the optimization of preclinical experiments and potentially reducing the animal testing. Acknowledgments: we would like to thank Prof. Paolo Magni (University of Pavia) for his support at the preliminary stage of this work.
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Reference: PAGE 33 (2025) Abstr 11454 [www.page-meeting.org/?abstract=11454]
Poster: Drug/Disease Modelling - Absorption & PBPK