Population Pharmacokinetic Modeling and Simulation for Dose Optimization of GB-5001, a Long-Acting Intramuscular Injection of Donepezil, in Healthy Participants.
IF 3.9
3区 医学
Q1 CLINICAL NEUROLOGY
引用次数: 0
Abstract
Introduction: GB-5001 is an intramuscular (IM) formulation of donepezil under development for the treatment of Alzheimer's disease. The objective of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the IM dosage of GB-5001 using bioequivalence (BE) simulation.
Methods: A population PK model of donepezil was developed using NONMEM. It was based on plasma concentration data from a Phase 1 dose escalation study, which involved a single administration of donepezil IM formulation at doses of 70, 140, and 280 mg, and the oral formulation at 10 mg. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, visual predictive checks, and bootstrapping. BE simulations were conducted using a parallel design between various doses of the IM formulation and the 10-mg dose of oral formulation.
Results: The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM (dual first-order absorption and simultaneous zero-order absorption with lag time) and oral (first-order absorption with lag time) formulations. Based on the simulation results, an IM dosage range of 210-215 mg in a sample size of over 92 was estimated to achieve a success rate of approximately 80% for BE.
Conclusion: The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials.
Trial registration: ClinicalTrials.gov identifier, NCT05525780.
为优化多奈哌齐长效肌内注射剂 GB-5001 在健康参试者中的剂量而进行的群体药代动力学建模和模拟。
简介：GB-5001是一种多奈哌齐的肌肉注射（IM）制剂，正在开发用于治疗阿尔茨海默病。本研究的目的是为多奈哌齐的IM和口服制剂建立群体药代动力学（PK）模型，并利用生物等效性（BE）模拟优化GB-5001的IM剂量：方法：使用 NONMEM 建立了多奈哌齐的群体 PK 模型。该模型基于一项 1 期剂量递增研究的血浆浓度数据，该研究涉及剂量为 70、140 和 280 毫克的多奈哌齐 IM 制剂和剂量为 10 毫克的口服制剂的单次给药。根据拟合优度图、条件加权残差、视觉预测检查和引导法对该模型进行了评估。在不同剂量的IM制剂和10毫克剂量的口服制剂之间采用平行设计进行了BE模拟：结果：多奈哌齐的 PK 用两室模型进行了最佳描述，该模型包含了 IM 制剂（双重一阶吸收和同时零阶吸收与滞后时间）和口服制剂（一阶吸收与滞后时间）的不同吸收室。根据模拟结果，在样本量超过 92 个的情况下，IM 剂量范围为 210-215 毫克，估计 BE 的成功率约为 80%：人群 PK 模型很好地解释了多奈哌齐在服用 IM 和口服制剂后的 PK。该模型可用于未来BE试验的设计和剂量选择：试验注册：ClinicalTrials.gov标识符，NCT05525780。
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来源期刊
Neurology and Therapy
CLINICAL NEUROLOGY-
CiteScore
5.40
自引率
8.10%
发文量
103
审稿时长
6 weeks
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Neurology and Therapy aims to provide reliable and inclusive, rapid publication for all therapy related research for neurological indications, supporting the timely dissemination of research with a global reach, to help advance scientific discovery and support clinical practice.
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