A 3D non-human primate digital model for pharmacokinetic prediction of intra-cerebrospinal fluid drug neuraxial dispersion
Abstract
Background: Intra-cerebrospinal fluid (CSF) drug delivery bypasses the blood-brain barrier, making it a promising route of delivery to treat central nervous system (CNS) diseases. Optimizing this delivery route is challenging because of complex interactions among drug kinetics, CSF flow dynamics and anatomical variations. Non-human primate (NHP) models provide an approximation to human physiology, making a suitable surrogate for studying intra-CSF drug dispersion. We present a NHP digital model for pharmacokinetic prediction of intra-CSF solute neuraxial dispersion that incorporates craniospinal compliance and other key physiological features.
Methods: A 3D subject-specific digital model of the NHP CSF system was formulated using a 3D multi-phase computational fluid dynamics (CFD) approach with flow and geometric boundary conditions using animal-specific in vivo MRI data. Initial digital model drug dispersion predictions were carried out assuming rigid dura and pial surfaces and verified by comparison to a 3D-printed NHP bench-top model replicating the in vivo measurements utilizing fluorescein as a surrogate drug tracer. Once verified, the digital model was extended to mimic craniospinal compliance by incorporating a dynamic mesh to allow dura surface motion that replicated the non-uniform CSF flow along the neuroaxis. Results were quantified over a one-hour period after a 1 mL drug injection via lumbar puncture needle in terms of spatial-temporal drug dispersion along the…
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