A predictive multiscale computational tool for simulation of lung absorption and pharmacokinetics and optimization of pulmonary drug delivery

用于模拟肺吸收和药代动力学的预测性多尺度计算工具， 肺部给药优化 项目概要/摘要： 通过口服吸入的肺部药物递送越来越多地用于治疗肺部疾病（例如， 哮喘和慢性阻塞性肺病）和将药物输送到体循环。到 达到预期的有效性和安全性的口服吸入药物，适当处置药物的目标 区域是必不可少的。由于复杂的药物和生理因素，涉及药物从 管理网站的目标区域，计算建模工具，迫切需要提供 涉及的输送过程的机制见解，并估计肺部药物输送的疗效， 准确和有效的方式。因此，在本项目中，我们提出开发一种新的预测多尺度 用于模拟递送、沉积、溶解、吸收、分布、代谢、排泄 在计算流体动力学（CFD）的整体框架内， PBPK-PD模型。我们将（1.）开发药物沉积的多模式计算模型， 经口吸入后的呼吸道;（2.）开发药物吸收和局部给药的多房室模型 肺组织中的PBPK（包括溶出模型和穿过空气-血液屏障的转运模型）; (3)开发全身PBPK模型，用于药物吸收后的分布、代谢和排泄， 呼吸道;整合药物吸收的房室吸收和转运模型， 胃肠道（已在CFDRC开发），以探索吞咽药物对药物的贡献 （4）将计算工具与药效学模型、气道力学模型和肺动力学模型相结合， 生理模型，以解释肺部药物的各种动态生理和病理因素 递送和吸收;（5）校准和验证两种仿制药的拟议工具：布地奈德和 福莫特罗;（6）对品牌和仿制药的药物递送、吸收和PK进行参数模拟 并评估化合物理化特性、制剂、生理环境和 病理因素;以及（7）开发仿制药、配方、装置、生理设置 以及吸入给药的病理因素。所提出的计算工具将提供一种机制- 的虚拟平台，以研究药物输送系统和生理系统之间的相互作用， 各种病理环境，以提供影响疗效和安全性的关键方面的机制见解 吸入药物产品，并指导肺部给药系统的最佳设计。的完成而 新的集成计算工具的开发将极大地促进剂量方案和药物开发的设计 通过识别影响吸入药物疗效和安全性的关键生物制药因素。软件工具 将被开发成一个商业产品（用户友好的GUI），旨在制药和生物医学 市场，以支持各种制药和生物医学应用，包括LADME-T研究， 体外-体内缩放、给药方案设计、肺部递送系统的优化以及安全性和 吸入性药物产品的功效评价。

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.