Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Biology and Bioinformatics
• Respiratory Pharmacology

Background:

• Physiologically based pharmacokinetic (PBPK) modeling is advancing, enabling predictions for various drug administration routes, including inhalation for respiratory diseases and systemic delivery.
• Inhalation offers a promising route for rapid systemic drug delivery, particularly for conditions requiring systemic exposure.

Purpose of the Study:

• To develop and validate a PBPK model for predicting plasma and tissue concentrations of the PI3Kδ inhibitor nemiralisib following inhalation administration.
• To mechanistically describe pulmonary absorption, systemic distribution, and oral absorption of nemiralisib after inhalation.

Main Methods:

• A PBPK model was constructed using GastroPlus®, incorporating detailed pulmonary absorption and systemic distribution mechanisms.
• Model validation was performed using clinical data from intravenous, oral, and inhalation administration of nemiralisib, alongside bronchoalveolar lavage fluid data.
• Novel parameters, including lung systemic absorption rate constants and the specific permeability-surface area product per tissue cell volume (SpecPStc), were implemented.

Main Results:

• The inhaled PBPK model demonstrated accurate predictions of plasma and bronchoalveolar lavage fluid concentrations in humans.
• Tissue concentration predictions were validated using rat intravenous infusion data, confirming the model's ability to predict systemic disposition.
• The model successfully assessed pulmonary drug absorption and predicted tissue distribution.

Conclusions:

• Mechanistic inhaled PBPK models, like the one developed, can be utilized for cross-molecule assessments of lung retention and systemic exposure.
• These models support evaluations in both pharmacology and toxicology, potentially aiding in clinical indication selection.
• The developed PBPK model provides a robust tool for understanding nemiralisib's disposition following inhalation.