A predictive multiscale computational tool for simulation of lung absorption and pharmacokinetics and
optimization of pulmonary drug delivery
Project Summary/Abstract:
Pulmonary drug delivery via oral inhalation is increasingly used for both treatment of lung diseases (such as
asthma and chronic obstructive pulmonary disease) and in delivering drugs to the systemic circulation. To
reach the desired effectiveness and safety of orally inhaled drugs, appropriate disposition of drugs in targeted
region is essential. Due to complex pharmaceutical and physiological factors involving drug transfer from the
administration site to the target region, computational modeling tools are urgently required to provide
mechanistic insights of involved delivery processes and to estimate efficacy of pulmonary drug delivery in an
accurate and efficient manner. Therefore, in this project, we propose to develop a novel predictive multiscale
computational tool to simulate delivery, deposition, dissolution, absorption, distribution, metabolism, excretion,
and actions of inhaled drug products within an integral framework of computational fluid dynamics (CFD) and
PBPK-PD models. We will (1.) develop multimodal computational models of drug deposition in the entire
respiratory tract after oral inhalation; (2.) develop an multi-compartmental model for drug absorption and local
PBPK in the lung tissue (which includes a dissolution model and a transport model across the air-blood barrier);
(3) develop a whole body PBPK model for drug distribution, metabolism, and excretion after absorption from
the respiratory tract; integrate a compartmental absorption and transit model for drug absorption from the
gastrointestinal tract (already developed at CFDRC) to explore the contribution of the swallowed drug to drug
PK; (4) integrate the computational tool with pharmacodynamics model, airway mechanics model and lung
physiology model to account for various dynamic physiological and pathological factors on pulmonary drug
delivery and absorption; (5) calibrate and validate the proposed tool for two generic drugs: budesonide and
formoterol; (6) conduct parametric simulations of drug delivery, absorption, and PK for brand and generic drugs
and evaluate effects of compound physiochemical characteristics, formulations, physiological settings and
pathological factors; and (7) develop databases of generic drugs, formulations, devices, physiological settings,
and pathological factors for inhalation delivery. The proposed computational tool will provide a mechanism-
based virtual platform to investigate interactions between drug delivery systems and physiological systems in
various pathological settings, to provide mechanistic insights into key aspects affecting efficacy and safety of
inhaled drug products, and to guide optimal designs of pulmonary drug delivery systems. The accomplishment
of the novel integrated computational tool will greatly facilitate design of dose regimen and drug development
by identifying key biopharmaceutical factors affecting efficacy and safety of inhaled drugs. The software tool
will be developed into a commercial product (user-friendly GUI ) aiming at pharmaceutical and biomedical
markets to support a variety of pharmaceutical and biomedical applications, including LADME-T investigation,
in vitro-in vivo scaling, dose regimen design, optimization of pulmonary delivery systems, and safety and
efficacy evaluation for inhaled drug products.
