Integration of Drug Release and Permeability with Systems Data Relevant to PBPK Model of Nose-to-Brain Axis and Verification Using Clinical Data

将药物释放和渗透性与鼻-脑轴 PBPK 模型相关的系统数据集成并使用临床数据进行验证

• 批准号: 10701846
• 负责人: Kayode Ogungbenro
• 金额: $ 26.44万
• 依托单位: UNIVERSITY OF MANCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701846
• 关键词: Integration; Drug; Release; Permeability; Systems

Project Summary Intranasal (IN) drug delivery is an attractive route as it avoids the hepatic first-pass effect and has a rapid-onset of action due to direct access to central nervous system (CNS). It has been suggested as a route to achieve effective drug concentration for treatment of neurological disorders where drug distribution to the CNS following delivery by other routes may be challenging due to the presence of blood-brain-barrier (BBB) and/or efflux transporters that reduce drug CNS exposure. Office of Generic Drugs (OGD) has prioritised access to generic drugs to ensure safe and effective use in patients. The importance of generic drugs has also been recognised by the FDA through the Generic Drug User Fee Amendments (GDUFA). Mechanistic tools such as physiologically-based pharmacokinetic (PBPK) models will further ensure development of quality, safe and effective generic drugs for delivery by IN route. Currently, there is no PBPK model in the literature that adequately accounts for important components such as direct nose-to-brain pathway, the role of transporters in the CNS drug disposition, the role of complex absorption process and the interplay between all these dynamic processes. In this project PBPK models for drugs delivered by IN route will be developed, linking the nose-to-brain pathway to the disposition of drug within the CNS and the rest of the body. This approach is based on in vitro-in vivo extrapolation (IVIVE) principles and builds on our current project on development of IVIVE-PBPK models for CNS drug disposition to link cerebrospinal fluid to localized brain concentration for compounds with mild-to- moderate efflux liabilities. In our proposal we will focus on three drugs: zolmitriptan, naloxone and oxycodone. Literature in vitro and clinical data will be used for initial model development; however, gaps will be filled with experimental data generated within this project. Proteomics data from olfactory region of human tissue will be generated and implemented in the model to account for the role of transporters in drug uptake. A prospective dedicated clinical trial following intravenous and IN delivery of three selected drugs will be used as an independent dataset for model validation and qualification. These data are critical for PBPK-driven deconvolution which is necessary to account for entry rate of the drugs following intranasal delivery, which will also be useful to explore complex interplay between permeability and transporter kinetics. All our methods and codes will be published for open access by PBPK users and commercial platform developers to create an immediate path for practical application by pharmaceutical scientists.

项目概要 鼻内（IN）药物递送是一种有吸引力的途径，因为它避免了肝脏首过效应并且 由于直接进入中枢神经系统（CNS），因此起效迅速。它一直 建议作为达到治疗神经系统疾病的有效药物浓度的途径 通过其他途径给药后药物分布至中枢神经系统可能会受到影响的疾病 由于血脑屏障（BBB）和/或外排转运蛋白的存在而具有挑战性 减少药物中枢神经系统暴露。仿制药办公室 (OGD) 优先考虑仿制药 确保患者用药安全、有效。仿制药的重要性也凸显 通过仿制药使用者费用修正案 (GDUFA) 获得 FDA 认可。 基于生理的药代动力学（PBPK）模型等机制工具将进一步 确保开发优质、安全、有效的仿制药，并通过 IN 途径输送。 目前，文献中还没有充分考虑重要因素的 PBPK 模型。 成分，例如直接鼻到脑通路、转运蛋白在中枢神经系统药物中的作用 处置、复杂吸收过程的作用以及所有这些之间的相互作用 动态过程。在这个项目中，通过 IN 途径输送药物的 PBPK 模型将是 开发了将鼻子到大脑的通路与中枢神经系统内药物的处置联系起来的技术 身体的其余部分。该方法基于体外体内外推法 (IVIVE) 原理和 建立在我们当前开发用于中枢神经系统药物处置的 IVIVE-PBPK 模型的项目的基础上 将脑脊液与具有轻度至-的化合物的局部脑浓度联系起来 适度的外流负债。在我们的提案中，我们将重点关注三种药物：佐米曲普坦、纳洛酮 和羟考酮。体外文献和临床数据将用于初始模型开发； 然而，该项目中产生的实验数据将填补空白。蛋白质组学 来自人体组织嗅觉区域的数据将在模型中生成和实施 解释转运蛋白在药物吸收中的作用。前瞻性专门临床试验 静脉内和 IN 输送三种选定药物后将作为独立药物使用 用于模型验证和鉴定的数据集。这些数据对于 PBPK 驱动至关重要 解卷积是考虑鼻内药物进入率所必需的 传递，这也将有助于探索渗透性和渗透性之间复杂的相互作用 转运动力学。我们所有的方法和代码都将由 PBPK 发布以供开放获取 为用户和商业平台开发者创建一条实用的直接路径 制药科学家的应用。