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 (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) 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. BrainECF, brainICF and CSFSAS 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 CSFSAS PK profiles that were consistently above IC50. Conclusion This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSFSAS 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.

An Improved In Vitro Blood-Brain Barrier Model for the Evaluation of Drug Permeability Using Transwell with Shear Stress

“…To compare the measured in vitro results with the in vivo data, we collected unbound plasma-cerebrospinal fluid (CSF) partition coefficient (K p,uu,CSF ) values from published studies [ 29 , 30 , 31 , 32 ]. The K p,uu,CSF values are usually defined as the ratio of the free CSF concentration to the free plasma concentration at equilibrium [ 33 ].…”

“…Bars represent the standard deviation ( n = 3). ( b ) The comparison between the in vitro P app value and in vivo K p,uu,CSF values [ 29 , 30 , 31 , 32 ] from different species including rat, mouse, monkey, and human. Each value represents the mean value.…”

“…Each value represents the mean value. The in vivo K p,uu,CSF values for the following symbols were obtained from other studies: * [ 31 ], # [ 29 ], † [ 30 ], ‡ [ 32 ].…”

“…N/A: not available. 1 [ 29 ], 2 [ 30 ], 3 [ 31 ], 4 [ 32 ]. The data were calculated, wherein the provided ratios of the total concentration in plasma to cerebrospinal fluid and unbound fractions were multiplied to obtain the final values.…”

Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice

“…However, these models do not distinguish the brain cells, brain ICF and brain ECF [ 32 , 58 ], while also do not account for the presence of lysosomes and non-specific binding [ 10 , 32 , 58 ]. Explicit distinction between all CNS physiological compartments, particularly the main target sites: brain ECF and brain ICF , is very relevant for more accurate assessment of the concentration-effect relationship [ 63 ]. Our LeiCNS-PK3.0 model inputs are physiological parameters, drug physicochemical properties, and K p,uu values, which can be obtained from in vivo , in vitro [ 64 ], or in silico [ 65 ] studies.…”