Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs

Abstract

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier–Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system’s components taken in isolation.

The Effect of Pulsatile Flow on Intrathecal Drug Delivery in the Spinal Canal

“…41,42 The steady streaming method was used to model solute dispersion in oscillatory flow. 11,20 In our study, parameters for mesh discretization and time-step integration were selected carefully, so that the numerical simulation was reproducible and mesh independent. The numerical solutions executed with 500,000 mesh cells and time steps of 0.05 s agreed reasonably well with data of experiments.…”

Advances in intrathecal drug delivery

“…The model was used to compare drug distribution with slow vs. instantaneous bolus injection. The findings indicate that chronically, drug distribution is more influenced by catheter tip orientation, pulsation, and breathing than injection speed, but that bolus dosing is more likely to travel farther from the catheter tip [10].…”

“…Several reports were published this year involving the investigation of drug flow kinetics. Kuttler et al [10] published a study using a biophysical model to investigate intrathecally administered drug pharmacokinetics. They incorporated geometry reconstructed from MRI data and dynamics controlled by transient Navier-Stokes equations to develop a three-dimensional computational fluid dynamics model of the spinal canal.…”

Computational Fluid Dynamics for the Assessment of Cerebrospinal Fluid Flow and Its Coupling with Cerebral Blood Flow

“…The authors cited the simplification of the domain geometry, the unknown structural characteristics of the arachnoiditis, as well as the linear elastic material properties used for the spinal cord as limitations of the study. In 2010, three CFD studies on CSF flow in the spinal SAS were published [48][49][50]. Among these, the work of Kuttler et al on the analysis of drug distribution after intrathecal drug administration (i.e.…”

“…Among these, the work of Kuttler et al on the analysis of drug distribution after intrathecal drug administration (i.e. drug delivery into the spinal SAS) was notable [50]. The authors generated a simplified 3D spinal domain based on data from the Visible Human Project [45] and imposed temporal flow profiles obtained via velocimetric MRI at the superior end of the domain.…”