Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer's Disease, Using the Physiologically Based LeiCNS-PK3.0 Model

Abstract

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 IC₅₀ 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 IC₅₀ values were not reached. Semagacestat brain PK plateau levels were below the IC₅₀ 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.

Keywords: Alzheimer’s; aging; physiologically based pharmacokinetics.