Feasibility of predicting regional lung exposure from systemic pharmacokinetic data of generic OIDPs via population pharmacokinetic modeling and non-compartmental approaches

通过群体药代动力学模型和非房室方法根据仿制药 OIDP 的全身药代动力学数据预测局部肺暴露的可行性

• 批准号: 10797284
• 负责人: Jurgen Bernd Bulitta
• 金额: $ 25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797284
• 关键词: Feasibility; predicting; regional; lung; exposure

Project Summary/Abstract Chronic respiratory tract diseases such as asthma are common and significantly affect the quality of patient lives. While effective and safe asthma medications are urgently needed, they pose a significant financial burden for patients. Moreover, the current regulatory pathway, the so-called “weight-of-evidence” approach, carries a considerable economic risk for generic drug developers. This presents an impediment for bringing cost-effective, safe and efficacious generic orally inhaled drug products (OIDPs) to the market. Therefore, systematically evaluating novel approaches that can reliably support the development and regulatory assessment of generic OIDPs is essential. This project will leverage innovative modeling and simulation strategies to evaluate whether population pharmacokinetic (PK) modeling and non-compartmental analysis (NCA) approaches based on plasma concentrations allow reliable conclusions on the bioequivalence of two OIDPS in the lung. Active pharmaceutical ingredients (APIs) with a range of physicochemical properties that are used in OIDPs will be studied through computer simulations. In Task 1, this project will develop lung physiologically-based PK (PBPK) models that can simulate both the local drug exposure profiles at different regions of the lung and plasma drug concentration profiles. These PBPK models will contain five or more lung compartments, reflecting the 23 physiological generations of the lung. Inhaled drug deposition in various lung regions will be implemented as a function of the particle size distribution. Further, the lung PBPK models will account for the total lung dose, dissolution kinetics, permeation, perfusion, as well as (for the upper airways) mucociliary clearance. These lung PBPK models will be used to simulate realistic plasma PK datasets for Test and Reference OIDPs with systematically varied properties, in the presence and absence of charcoal to block oral absorption. Simulated local drug exposure profiles at various regions of the lung will serve as the therapeutically relevant, true, pulmonary comparators. Studies in Task 2 will use the PBPK-simulated drug exposure profiles in plasma as relevant inputs. The main goal of this task is to probe whether, and with which level of granularity, population PK can detect differences in regional pulmonary exposure by modeling plasma concentration-time profiles of Test and Reference OIDPs. In addition to modeling pulmonary absorption via population PK, the less complex NCA with established and novel parameters (e.g. partial AUCs during the absorption phase) will be applied using the same data sets. This will allow one to compare the capabilities, strengths, weaknesses, and robustness of both approaches for detecting differences in regional pulmonary exposure. In Task 3, key findings across all simulated APIs, OIDPs, conditions, and study designs will be summarized to create robust and generalizable conclusions to support PK approaches and potential BE criteria for lung BE testing. In Task 4, the report, simulated datasets, PBPK, population PK and NCA models and results will be made available in an electronic database to the FDA.

项目总结/摘要 哮喘等慢性呼吸道疾病很常见，严重影响患者的生活质量。 虽然迫切需要有效和安全的哮喘药物，但它们对患者造成了重大的经济负担。 患者此外，目前的监管途径，即所谓的“证据权重”方法， 这对仿制药开发商来说是相当大的经济风险。这阻碍了将具有成本效益的， 安全和有效的通用口服吸入药物产品（OIDP）的市场。因此，系统地 评估能够可靠支持仿制药开发和监管评估的新方法 OIDP是必不可少的。该项目将利用创新的建模和仿真策略来评估是否 群体药代动力学（PK）建模和非房室分析（NCA）方法，基于 血浆浓度允许关于两种OIDPS在肺中的生物等效性的可靠结论。活性 OIDP中使用的具有一系列理化性质的药物成分（API）将被 通过计算机模拟研究。在任务1中，本项目将开发基于肺生理学的PK（PBPK） 可以模拟肺不同区域的局部药物暴露曲线和血浆药物暴露曲线的模型 浓度分布这些PBPK模型将包含五个或更多个肺隔室，反映23个肺隔室。 肺的生理世代。吸入药物在各个肺部区域的沉积将作为 粒度分布的函数。此外，肺PBPK模型将考虑总肺剂量， 溶解动力学、渗透、灌注以及（对于上呼吸道）粘膜纤毛清除。这些肺 PBPK模型将用于模拟受试和参比OIDP的真实血浆PK数据集， 在存在和不存在木炭的情况下，系统地改变性质以阻止口服吸收。模拟 在肺的各个区域的局部药物暴露曲线将作为治疗相关的，真实的， 肺对照药物。任务2中的研究将使用PBPK模拟的血浆药物暴露曲线， 相关投入。这项任务的主要目标是探索人口PK是否以及在何种粒度级别上 通过对受试制剂的血浆浓度-时间曲线进行建模， 和参考OIDP。除了通过群体PK对肺吸收进行建模外， 将使用已确定的新参数（例如吸收阶段的部分AUC）， 相同的数据集。这将允许比较两者的能力、优势、劣势和健壮性 检测区域肺部暴露差异的方法。在任务3中，所有模拟的关键发现 将总结API、OIDP、条件和研究设计，以得出稳健和可推广的结论 支持肺BE检测的PK方法和潜在BE标准。在任务4中，报告，模拟数据集， PBPK、群体PK和NCA模型和结果将在电子数据库中提供给FDA。