Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary Absorption, Systemic Distribution, and Oral Absorption

Abstract

Background and objectives: Physiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.

Methods: A PBPK model was built in GastroPlus^® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.

Results: The inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.

Conclusions: Fully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.

Fig. 1

Conceptual diagram of an inhaled + oral (ACAT) + systemic (tissues) PBPK model. ACAT advanced compartmental absorption and transit, PBPK physiologically based pharmacokinetic, PStc permeability-surface area product, Q tissue blood flow, V tissue volume

Fig. 2

Simulated plasma concentrations (solid line) following an intravenous infusion dose of approximately 10 μg compared with measured concentrations (symbols) in individual healthy volunteers (a–f represent subjects 1–6, respectively)

Fig. 3

Predicted mass of nemiralisib in liver (solid line), muscle (dotted line) and adipose (dashed line) versus time following an intravenous infusion dose of approximately 10 μg in a single healthy volunteer using a permeability-limited tissue model

Fig. 4

Simulated plasma concentrations (solid line) following an oral solution dose of approximately 800 μg compared with measured concentrations (symbols) in individual healthy volunteers (a–f represent subjects 1–6, respectively)

Fig. 5

Predicted plasma concentrations (solid line) following an inhalation dose of approximately 1000 μg compared with measured concentrations (symbols) in individual healthy volunteers (a–f represent subjects 1–6, respectively)

Fig. 6

Predicted mass of nemiralisib in thoracic mucus (solid line), bronchiolar mucus (dotted line), thoracic tissue (dashed line) and bronchiolar tissue (dashed/dotted line) versus time in human following an inhalation dose of approximately 1000 μg in a single healthy volunteer

Fig. 7

Predicted mass of nemiralisib in liver (solid line), muscle (dotted line), adipose (dashed line) and skin (dashed/dotted line) versus time following an inhalation dose of approximately 1000 μg in a single healthy volunteer using a permeability-limited tissue model