Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model

BACKGROUND: Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain(ECF)) and intracellular (brain(ICF)) fluids and cerebrospinal fluid of the subarachnoid space (CSF(SAS)) 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(50) values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. RESULTS: The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. Brain(ECF), brain(ICF) and CSF(SAS) PK profile relationships were different between the drugs. Aging and Alzheimer’s had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC(50) values were not reached. Semagacestat brain PK plateau levels were below the IC(50) of gamma-secretase for half of the interdose interval, unlike CSF(SAS) PK profiles that were consistently above IC(50.) CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSF(SAS) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11095-022-03281-3.