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 鼻腔给药是一种有吸引力的途径，因为它避免了肝脏首过效应和 由于直接接触到中枢神经系统(CNS)，有快速起效的作用。一直以来 建议作为治疗神经系统疾病的有效药物浓度的一种途径 通过其他途径将药物分配到中枢神经系统的障碍 由于血脑屏障(BBB)和/或外流转运体的存在而具有挑战性 减少药物对中枢神经系统的暴露。仿制药办公室(OGD)已将获得仿制药列为优先事项 确保患者安全有效地使用药物。仿制药的重要性也 通过仿制药使用费修正案(GDUFA)得到FDA的认可。 基于生理的药代动力学(PBPK)模型等机械工具将进一步 确保开发高质量、安全、有效的仿制药，通过IN路线交付。 目前，文献中没有一个PBPK模型能够充分解释重要的 鼻脑直接通路、转运蛋白在中枢神经系统药物中的作用等成分 处置、复杂吸收过程的作用以及它们之间的相互作用 动态过程。在这个项目中，IN ROUTE运送的药物的PBPK模型将是 发展起来，将鼻到脑的通路与药物在中枢神经系统内的处置和 身体的其他部分。这种方法是基于体外-体内外推(IVIVE)原理和 建立在我们目前开发IVE-PBPK中枢药物处置模型的基础上 将脑脊液与局部脑浓度联系起来，以检测具有轻度至... 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。最初的模型开发将使用体外文献和临床数据； 然而，空白将被这个项目中产生的实验数据所填补。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并执行，以 说明转运蛋白在药物摄取中的作用。一项前瞻性的专门临床试验 在静脉注射和静脉注射后，三种选定的药物将作为独立的 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 去卷积，这是解释药物经鼻腔进入的速度所必需的 传输，这也将有助于探索渗透性和 转运蛋白动力学。我们的所有方法和代码都将由PBPK发布以供开放获取 为用户和商业平台开发者创造一条切合实际的立竿见影之路 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.