Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations

Mohammed A A Saleh,Chi Fong Loo,Jeroen Elassaiss-Schaap,Elizabeth C M De Lange

doi:10.1007/s10928-021-09768-7

Abstract

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug’s physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.

Highlights

Central nervous system (CNS) pharmacokinetic (PK) profiling, though challenging, remains critical for drug development
For validating the rat version of LeiCNS-PK3.0, only inhouse data were used, where individual unbound PK profiles were simultaneously measured in the same animal under controlled conditions in plasma and in multiple central nervous system (CNS) locations: brain extracellular fluid (ECF), lateral ventricles (LV), and cisterna magna (CM) using microdialysis, in addition to total brain concentrations, which were measured with the brain homogenate method
LeiCNS-PK3.0 simulations showed that altered cerebrospinal fluid (CSF) dynamics resulted in a shift in the drug concentration ratio of brain ECF-to-subarachnoid space (SAS) CSF, where SAS CSF PK profiles but not brain ECF PK profiles were affected

Summary

Introduction

Central nervous system (CNS) pharmacokinetic (PK) profiling, though challenging, remains critical for drug development. Two PK profiles can be distinguished in the CNS: brain and cerebrospinal fluid (CSF) PK profiles. In CNS drug development, compounds are selected that optimize brain PK profile, since brain cells and extracellular fluid (ECF) represent the major site of drug (side-) effects. Suboptimal drug exposure in brain has resulted in clinical trial failure and has contributed to the high attrition rate of the CNS drugs in development [1]. CSF represents a relatively accessible matrix to sample the CNS, mainly via lumbar puncturing.

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