Data-fusion based platform development of population PKPD modeling and statistical analysis for bioequivalence assessment of long-acting injectable products

基于数据融合的群体 PKPD 建模和统计分析平台开发，用于长效注射剂产品的生物等效性评估

• 批准号: 9060079
• 负责人: Seongkyu Yoon
• 金额: $ 19.99万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060079
• 关键词: Data; fusion; based; platform; development

Summary The active pharmaceutical ingredient (API) in long acting injectable (LAI) products is usually delivered into the system circulation in form of microspheres. Currently, bioequivalence guidance of generic formulations requires both qualitatively (Q1) and quantitatively (Q2) the same as the reference-listed drug. Usually parallel bioequivalence (BE) study is recommended. This is very challenging due to high inter-subject variability, complex pharmacokinetic and pharmacodynamic (PKPD) profiles, study length and expenditure. This research proposes data-fusion based platform for population PKPD modeling and statistical analysis to assist development of generic LAI products. The integrated platform of mechanistic and data-driven models is developed for bioequivalence testing and covariate assessment of generic LAI products. The new platform will be validated with the target product and its generic forms. The deterministic models are the existing population PKPD models and they are supplemented with statistical process models to minimize uncertainties into account. Subject Evolution Modeling (SEM), Subject Level Modeling (SLM), and prediction modeling will allow all challenges of clinical evaluations to be addressed with minimum uncertainty and high level of robustness. The integrated models are imbedded in Monte Carlo simulation to determine feasible ranges of covariate variability, which are used for optimizing drug dosage while meeting safety and efficacy requirement.

总结 长效可注射（LAI）产品中的活性药物成分（API）通常被递送到注射器中。 微球形式的系统循环。目前，仿制药的生物等效性指南 要求在定性（Q1）和定量（Q2）方面与参比药物相同。通常平行 建议进行生物等效性（BE）研究。由于受试者间的高度变异性，这是非常具有挑战性的， 复杂的药代动力学和药效学（PKPD）特征、研究时长和费用。本研究 提出了基于数据融合的人口PKPD建模和统计分析平台， 开发通用LAI产品。机械和数据驱动模型的集成平台是 开发用于仿制LAI产品的生物等效性测试和协变量评估。新平台将 使用目标产品及其通用形式进行验证。确定性模型是现有的人口 PKPD模型，并辅以统计过程模型，以尽量减少不确定性， 帐户.主题演化建模（SEM）、主题级建模（SLM）和预测建模将允许 以最小的不确定性和高水平的稳健性解决临床评价的所有挑战。 集成模型嵌入蒙特卡罗模拟，以确定协变量的可行范围 可变性，用于优化药物剂量，同时满足安全性和有效性要求。