Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs.
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.
Modeling and Simulation, Novartis Pharma AG, Novartis Campus, 4056 Basel, Switzerland.
Andreas
A
Kuttler
Thomas
T
Dimke
Steven
S
Kern
Gabriel
G
Helmlinger
Donald
D
Stanski
Luca A
LA
Finelli
D000818:Animals; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D006801:Humans; D057446:Hydrodynamics; D007278:Injections, Spinal; D008953:Models, Anatomic; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000134:cerebrospinal fluid*; D010599:Pharmacokinetics; D013115:Spinal Canal / Q000033:anatomy & histology* / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations