Gueorguieva Ivelina, Chow Kay, Chua Laiyi, Shcherbinin Sergey, Zimmer Jennifer A, Evans Cynthia D, Wang Hong, Nery Emel Serap Monkul, Brooks Dawn A, Sims John R
Department of Global Pharmacokinetics/Pharmacodymanics/Pharmacometrics, Eli Lilly and Company, Bracknell, Berkshire, UK.
Department of Global Pharmacokinetics/Pharmacodymanics/Pharmacometrics, Eli Lilly and Company, Singapore, Singapore.
Alzheimers Dement. 2025 Jul;21(7):e70491. doi: 10.1002/alz.70491.
These analyses aimed to identify factors impacting donanemab exposure, amyloid plaque, and clinical efficacy in early symptomatic Alzheimer's disease using a population pharmacokinetic/pharmacodynamic (PK/PD) approach.
Analyses included donanemab trial participants (NCT02624778; NCT03367403; NCT04640077; NCT04437511). Dose- and exposure-response relationships were characterized relative to amyloid plaque lowering using indirect response PK/PD and disease progression models.
Donanemab population PK was described by a biphasic distribution with an estimated terminal elimination half-life of approximately 12.1 days for a typical participant (72 kg body weight, 1:2560 maximum antidrug antibody [ADA] titer). Amyloid reduction was associated with maintaining median serum donanemab concentrations over 15 µg/mL (95% confidence interval: 8.54, 18.0). After completing active treatment, simulations showed an estimated plaque reaccumulation rate (median, 95% confidence interval) of 2.8 (2.16, 3.11) Centiloids/year. The donanemab disease progression model showed a clear treatment effect.
These donanemab models can inform dosing strategies in future clinical trials.
Weight-based and flat dosing had similar exposure metrics; flat dosing was adopted. Donanemab exposure was influenced by weight and titer (not clinically relevant). 2.8 Centiloids/year amyloid reaccumulation rate observed upon donanemab treatment completion. Around 30% reduction in disease progression rate on treatment for integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).
这些分析旨在采用群体药代动力学/药效学（PK/PD）方法，确定影响早期有症状阿尔茨海默病中多奈哌齐暴露量、淀粉样斑块和临床疗效的因素。
分析纳入了多奈哌齐试验参与者（NCT02624778；NCT03367403；NCT04640077；NCT04437511）。使用间接响应PK/PD和疾病进展模型，对剂量与暴露-反应关系相对于淀粉样斑块降低情况进行了表征。
多奈哌齐群体药代动力学可用双相分布描述，典型参与者（体重72千克，最大抗药物抗体[ADA]滴度为1:2560）的估计终末消除半衰期约为12.1天。淀粉样蛋白减少与血清多奈哌齐浓度中位数维持在15微克/毫升以上相关（95%置信区间：8.54，18.0）。完成活性治疗后，模拟显示估计的斑块再积累率（中位数，95%置信区间）为每年2.8（2.16，3.11）Centiloids。多奈哌齐疾病进展模型显示出明显的治疗效果。
这些多奈哌齐模型可为未来临床试验中的给药策略提供参考。
基于体重给药和平板给药具有相似的暴露指标；采用平板给药。多奈哌齐暴露受体重和滴度影响（临床意义不大）。多奈哌齐治疗完成后观察到淀粉样蛋白再积累率为每年2.8 Centiloids。综合阿尔茨海默病评定量表（iADRS）和临床痴呆评定量表-框和（CDR-SB）治疗时疾病进展率降低约30%。
