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

摘要 长效可注射剂(LAI)产品中的有效药物成分(API)通常被输送到 微球形式的系统循环。目前，仿制制剂的生物等效性指南 在定性(Q1)和定量(Q2)上都要求与参考上市药物相同。通常是平行的 建议进行生物等效性(BE)研究。由于学科间的高度可变性，这是非常具有挑战性的， 复杂的药代动力学和药效学(PKPD)概况、研究时间和费用。这项研究 提出了基于数据融合的人口PKPD建模和统计分析平台 开发非专利LAI产品。机械模型和数据驱动模型的集成平台是 开发用于非专利LAI产品的生物等效性测试和协变量评估。新平台将 通过目标产品及其仿制形式进行验证。确定性模型是现有的总体 PKPD模型，并补充了统计过程模型，以将不确定性降至最低 帐号。主题演化建模(SEM)、主题级别建模(SLM)和预测建模将允许 临床评估的所有挑战都应以最小的不确定性和高水平的稳健性来解决。 将集成后的模型嵌入蒙特卡罗模拟中，确定协变量的可行范围 可变性，用于在满足安全性和有效性要求的同时优化药物剂量。

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.