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.

Fig. 1

The physiologically based LeiCNS-PK3.0 model structure. This model uses drug physicochemical and biological properties and CNS physiology that together govern the CNS PK of a small molecule drug. This allows the translation of PK predictions in multiple CNS compartments between species and between physiological conditions (health, disease, etc.).

Fig. 2

Simulated unbound PK profiles of the four marketed AD drugs at brain_ECF, brain_ICF, and subarachnoid space (CSF_SAS) of CHY (green), CHE (blue), and AD (red) populations. Aging and AD pathophysiological changes have a minor impact on brain_ECF, brain_ICF, and CSF_SAS PK profiles. Model simulations were performed using the clinical dosing regimens. For each drug, the plasma PK input in the model was based on plasma PK data of CHE or AD patients. Thus, any change of PK profile is attributed to changes of CNS physiology. Please note the different y-axis scale of every panel. Brain_ECF: brain extracellular fluid, brain_ICF: brain intracellular fluid, CSF_SAS: cerebrospinal fluid of the subarachnoid space, CHY: cognitively healthy young adults, CHE: cognitively healthy elderly.

Fig. 3

AD predicted PK profiles of the 4 marketed AD drugs at the brain_ECF, brain_ICF, and CSF_SAS versus the IC₅₀ of the respective drug target. Target site concentrations are the driver of drug effect and should therefore be evaluated during early stages of drug development. The predicted PK profiles of rivastigmine are below the IC₅₀ of acetylcholinesterase. Memantine PK profile at the CSF_SAS and not at the brain_ECF were lower than the IC₅₀ of NMDA receptor, which might imply that lumbar CSF_SAS drug concentration is an inaccurate surrogate of that of brain_ECF.

Fig. 4

Semgacestat PK profiles of cognitively healthy (CHY) young volunteers (green) and AD patients (red) at the brain_ECF, brain_ICF and at the CSF_SAS. The black dots in the CSF_SAS are semagacestat concentrations at a single dose of 140 mg, measured in CSF samples from CHY volunteers (34). The blue horizontal dashed line represents the paradoxical value used by de Strooper (18) of notch inhibition, while black dashed line represents the IC₅₀ of gamma-secretase inhibition by semagacestat. These simulations support the take home messages of the de Strooper (18) analysis on the importance of addressing the fluctuation of the drug concentrations and, in addition, indicate the importance of considering the steady state, potentially disease-altered, PK profiles at the target sites in the brain_ECF and brain_ICF.