Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study.
Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study.
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DOI：
10.1002/trc2.12329
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发表时间：
2022
影响因子：
4.8
通讯作者：
Territo, Paul R
中科院分区：
文献类型：
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作者：
Onos, Kristen D;Quinney, Sara K;Jones, David R;Masters, Andrea R;Pandey, Ravi;Keezer, Kelly J;Biesdorf, Carla;Metzger, Ingrid F;Meyers, Jill A;Peters, Johnathon;Persohn, Scott C;McCarthy, Brian P;Bedwell, Amanda A;Figueiredo, Lucas L;Cope, Zackary A;Sasner, Michael;Howell, Gareth R;Williams, Harriet M;Oblak, Adrian L;Lamb, Bruce T;Carter, Gregory W;Rizzo, Stacey J Sukoff;Territo, Paul R
过度兴奋和癫痫样活动在阿尔茨海默病（AD）患者中很常见，并与认知功能受损相关。抗癫痫药物左乙拉西坦（LEV）目前正在临床试验中评估其减少癫痫样活动和改善AD认知功能的能力。我们研究的目的是在AD的淀粉样蛋白生成小鼠模型中建立与LEV的药代动力学/药效学（PK/PD）关系，以使用晚发性阿尔茨海默病临床前测试核心的模型生物体开发和评价的严格临床前测试管道实现预测性临床前到临床的转化。采用了多层方法，包括活性药物成分的质量保证和质量控制、PK/PD建模、正电子发射断层扫描/磁共振成像（PET/MRI）、功能结局和转录组学。5XFAD小鼠用LEV长期治疗3个月，剂量与异速生长缩放至临床剂量范围的剂量一致。LEV的药代动力学表现出Cmax、AUC 0-∞和CL/F的性别差异，以及AUC 0-∞的剂量依赖性。以10、30、56 mg/kg长期给药后，PET/MRI示踪剂18 F-AV 45和18 F-FDG显示出特定的区域差异。LEV并未显着改善认知结果。通过nanoString进行的转录组学研究表明，与人类大脑区域和途径相关的基因表达的药物和剂量相关变化与18F-FDG摄取的变化一致。该研究代表了在5XFAD小鼠中LEV的PK/PD评估的第一份报告。总体而言，这些结果强调了基于剂量和性别的非线性动力学。5XFAD中10 mg/kg剂量的血浆浓度与用于轻度认知障碍研究的人血浆浓度重叠，而30和56 mg/kg剂量反映了用于治疗癫痫发作活动的剂量。治疗后基因表达分析表明，LEV剂量相关的免疫功能变化和与人类AD相关的神经元信号通路，并与局部18F-FDG摄取一致。总体而言，本研究强调了临床前研究中PK/PD关系的重要性，以告知临床研究设计。在5XFAD小鼠中观察到左乙拉西坦药代动力学的显著性别差异。5XFAD中10 mg/kg左乙拉西坦剂量的血浆浓度与临床使用的人血浆浓度重叠。与人脑区域和通路相关的基因表达的药物和剂量相关差异也与18F-氟脱氧葡萄糖摄取的脑区域特异性变化相似。
Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The anti‐seizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease Preclinical Testing Core. A multi‐tier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC0‐∞, and CL/F, and a dose dependence in AUC0‐∞. After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer 18F‐AV45, and 18F‐fluorodeoxyglucose (18F‐FDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drug‐ and dose‐related changes in gene expression relevant to human brain regions and pathways congruent with changes in 18F‐FDG uptake. This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted non‐linear kinetics based on dose and sex. Plasma concentrations of the 10 mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56 mg/kg doses were reflective of doses used to treat seizure activity. Post‐treatment gene expression analysis demonstrated LEV dose‐related changes in immune function and neuronal‐signaling pathways relevant to human AD, and aligned with regional 18F‐FDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice. Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic. Drug‐ and dose‐related differences in gene expression relevant to human brain regions and pathways were also similar to brain region–specific changes in 18F‐fluorodeoxyglucose uptake.