Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
PD-value B.V., Houten, The Netherlands.
Pharm Res. 2022 Jul;39(7):1303-1319. doi: 10.1007/s11095-022-03281-3. Epub 2022 May 23.
Very little knowledge exists on the impact of Alzheimer's disease on the CNS target site pharmacokinetics (PK).
To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer's patients using the physiologically based LeiCNS-PK3.0 model.
LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain) and intracellular (brain) fluids and cerebrospinal fluid of the subarachnoid space (CSF) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer's patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer's based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase.
The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. Brain, brain and CSF PK profile relationships were different between the drugs. Aging and Alzheimer's had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC values were not reached. Semagacestat brain PK plateau levels were below the IC of gamma-secretase for half of the interdose interval, unlike CSF PK profiles that were consistently above IC CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSF PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer's, this study shows that the impact of aging and Alzheimer's pathology on CNS distribution of the five drugs is insignificant.
关于阿尔茨海默病对中枢神经系统（CNS）靶部位药代动力学（PK）的影响，目前所知甚少。
使用基于生理学的 LeiCNS-PK3.0 模型，预测认知健康的年轻和老年人群以及阿尔茨海默病患者的 CNS PK。
LeiCNS-PK3.0 用于预测多奈哌齐、加兰他敏、美金刚、利伐斯的明和司来吉兰在年轻、老年和阿尔茨海默病患者的脑细胞外液（脑）和细胞内液（脑）以及蛛网膜下腔（CSF）中的 PK 特征。LeiCNS-PK3.0 的生理参数根据广泛的文献检索进行了老化和阿尔茨海默病的调整。临床剂量方案的平台期 CNS PK 特征与乙酰胆碱酯酶、丁酰胆碱酯酶、N-甲基-D-天冬氨酸或 γ-分泌酶的体外 IC 值相关。
所有药物的 PK 特征在平台水平和波动方面在 CNS 隔室之间均存在差异。脑、脑和 CSF 的 PK 特征与药物之间的关系不同。衰老和阿尔茨海默病对 CNS PK 几乎没有影响。利伐斯的明乙酰胆碱酯酶 IC 值未达到。司来吉兰脑 PK 平台水平在半日内剂量间隔内低于 γ-分泌酶的 IC，与 CSF PK 特征不同，后者始终高于 IC。
本研究深入了解了 CNS 隔室 PK 特征之间的关系，包括靶部位。CSF PK 似乎不能可靠地预测脑 PK。此外，尽管阿尔茨海默病患者的血脑屏障和脑特性发生了广泛变化，但本研究表明，衰老和阿尔茨海默病病理对五种药物在 CNS 中的分布的影响并不显著。
