Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model

Abstract

The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0). The bidirectional and site-dependent CSF movement was incorporated into LeiCNS-PK3.0 to create the new LeiCNS-PK“3.1” model. The physiological CSF movement rates in healthy rats that are unavailable from the literature were estimated by fitting the PK data of sucrose, a CSF flow marker, after intra-CSF administration. The capability of LeiCNS-PK3.1 to describe the PK profiles of other molecules was compared with that of the original LeiCNS-PK3.0 model. LeiCNS-PK3.1 demonstrated superior description of the CSF PK profiles of a range of small molecules after intra-CSF administration over LeiCNS-PK3.0. LeiCNS-PK3.1 also retained the same level of predictability of CSF PK profiles in cisterna magna after intravenous administration. These results support the theory of bidirectional and site-dependent CSF movement across the entire CSF space over unidirectional and constant CSF circulation in healthy rats, pointing out the need to revisit the structures and parameters of CSF compartments in CNS-PBPK models.

Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood–Brain Barrier and Assess Target Site Disposition

“…This assumption was based on an earlier theory called “third circulation” [ 84 ], which states that CSF is only produced by choroid plexus, and thus the movement of drug in the CSF compartments was unidirectional. This assumption was further challenged and corrected in the Lei-CNS 3.1 model to account for the bidirectional CSF flow [ 85 ]. Thus, overall, among all the CNS PBPK models discussed in the literature, the model by Vercheijden et al [ 28 ] was chosen because it has been scaled from adults to pediatric patients for acetaminophen, ibuprofen, naproxen, and meropenem over a wide age range, which implies the model structure is robust.…”

“…CSF data were thus used to qualify the performance of this translational approach. CSF cannot be considered a relevant compartment for antibiotics, antiepileptic, or analgesic drugs in which the concentration in the parenchymal extracellular fluid is probably more important [ 85 ]. Likewise, a concentration gradient exists between CSF and brain tissue, with the magnitude being determined by the relation of CSF bulk flow [ 88 ].…”

Toxicity studies on intrathecal injection of low dose of DMSO used for cryopreservation of human astrocytes in mice

“…Some predictions can be made for the exposure of the CNS to intended DMSO level. The average of total CSF volume in humans is generally quoted as approximately 130 ml 35,36 with a ow rate of 21-24 ml/h 37,38,39 which results with CSF turnover rate of 3-4 times a day 40 . Assuming the most stringent case of no distribution outside the CSF, an IT injection of AstroRx® contains a total of 47 mg of DMSO.…”

Mathematical modeling of transdermal delivery of topical drug formulations in a dynamic microfluidic diffusion chamber in health and disease

“…To test novel topical anandamide formulation for alleviating peripheral neuropathic pain Police and coworkers used also molecular docking methods and simulation [ 2 ]. The compartmental pharmacokinetic models (Physiologically-Based Pharmacokinetic Models) are used by other authors with a focus on blood-brain barrier/ blood-CSF-barrier penetration [ 6 , 7 ], or e.g. intestinal absorption [ 8 ].…”