Physiologically Based Pharmacokinetic Modeling to Investigate Regional Brain Distribution Kinetics in Rats

Abstract

Abstract. One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF LV , and CSF CM indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC 0−240 ratios of 121%, 28%, and 35% for brain ECF, CSF LV , and CSF CM , respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations.

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

“…The CNS portion of the model was based on validated parameters describing CNS and CSF physiology and anatomy (14). A schematic of this model is shown in Fig.…”

“…The approach mathematically describes physiological and molecular processes defining PK, integrating drug-specific properties (such as log P, Caco-2 cell apparent permeability, and affinities for transporters and metabolic enzymes) and patient-specific factors (such as height, weight, sex, organ volumes, and blood flow) (13). The model presented here is based on a full-body PBPK model supplemented with a 6-compartment model of the CNS and CSF, as previously described (14).…”

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…As in PBPK modeling, the explicit separation is made between drug and systems properties, it is a great translational tool. To date, many more or less complex (semi-)PBPK models have been published for CNS drug distribution [30][31][32][33][34]. Gaohua et al [33] published a human PBPK model with a few physiological CNS compartments.…”

“…Gaohua et al [33] published a human PBPK model with a few physiological CNS compartments. Other (semi-) PBPK models have been developed using extensive information obtained from preclinical species, with explicit inclusion of unbound drug concentrations [31,32]. To that end, the microdialysis technique [35] provided valuable data that were obtained in parallel in the multiple CNS compartments, to further pave the way toward the generic semi-PBPK CNS drug distribution model.…”

Investigation of Factors Affecting Microdialysis Probe Delivery and Recovery of Puerarin In Vitro

“…Usually, the real concentration of analyte in extracellular fluid (ECF) in vivo experiments can be calculated by dividing the sample concentration by delivery itself or the internal standard added in the perfusion solution [2][3][4][5]. However, it is only if there were no significant differences between delivery and recovery in vitro, can the delivery in vivo be considered as the recovery of free-form drug in ECF.…”