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

项目摘要 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， 由于直接进入中枢神经系统（CNS），具有快速起效的作用。已经 建议作为达到治疗神经系统疾病的有效药物浓度的途径 通过其他途径递送后药物分布到CNS的疾病可能 由于存在血脑屏障（BBB）和/或外排转运蛋白， 减少药物CNS暴露。仿制药办公室（OGD）优先考虑获得仿制药 确保患者用药安全有效。仿制药的重要性也 FDA通过仿制药用户费用修正案（GDUFA）认可。 诸如基于生理学的药代动力学（PBPK）模型的机制工具将进一步 确保开发出优质、安全和有效的非专利药品，用于IN途径。 目前，在文献中没有PBPK模型充分解释重要的 组分，如直接鼻-脑途径，转运蛋白在CNS药物中的作用 处置，复杂的吸收过程的作用和所有这些之间的相互作用 动态过程在本项目中，将为通过IN途径递送的药物建立PBPK模型， 开发，将鼻-脑途径与CNS内药物的处置和 身体的其余部分。该方法基于体外-体内外推（IVIVE）原理， 建立在我们目前开发IVIVE-PBPK模型用于CNS药物处置的项目上 将脑脊液与局部脑浓度联系起来， 适度的流出负债。在我们的提案中，我们将重点关注三种药物：佐米曲坦，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，将利用该项目产生的实验数据填补空白。Proteomics 来自人体组织的嗅觉区域的数据将在模型中生成和实现， 说明转运蛋白在药物摄取中的作用。一项前瞻性专门临床试验 在静脉内和IN递送三种选定的药物后， 用于模型验证和资格的数据集。这些数据对于PBPK驱动的 解卷积，这是解释鼻内给药后药物进入率所必需的 交付，这也将有助于探索渗透性和 转运体动力学我们所有的方法和代码都将由PBPK公开发布 用户和商业平台开发商创建一个实用的即时路径 制药科学家的应用。

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.