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      Insights from mathematical modeling for convection-enhanced intraputamenal delivery of GDNF

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          Abstract

          Glial cell line-derived neurotrophic factor (GDNF) is a potential therapy for Parkinson’s disease (PD) promoting survival and functional recovery of dopaminergic neurons when delivered to the degenerated striatum. To study the aspects of intraputamenal delivery of GDNF, a mathematical model of recombinant methionyl human GDNF (r-metHuGDNF) convection in the human putamen has been developed. The convection-enhanced delivery infusions of r-metHuGDNF were simulated at rates up to 5 μL/min. The high-rate infusions (≥1 μL/min) permit rapid and uniform distribution of drug with up to 75% of the distribution volume having a concentration within 5% of the infusate concentration. No relevant differences in distribution at infusion rates of 3 and 5 μL/min were found. The patterns of GDNF distribution were analyzed in relation to the anatomy of the posterior dorsal putamen, and a cylindrical shape was found to be preferable considering risks of target overflow. A magnetic resonance (MR) tracer Gd-DTPA (Magnevist®) was evaluated as a surrogate in clinical studies, and the most accurate prediction of GDNF distribution was calculated immediately after infusion. The clearance of GDNF from the striatum is confirmed to be slow, with a half-life of ca. 19 h.

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          Convection-enhanced delivery of macromolecules in the brain.

          R H Bobo, D W Laske, A Akbasak … (1994)
          For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.
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            Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo.

            Wei Lin, B Hoffer, E Lindqvist … (1995)
            Glial-cell-line-derived neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons and is expressed in the developing striatum. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substantia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.
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              Diffusion of macromolecules in the brain: implications for drug delivery.

              Philip G Thorne, Daniel Wolak (2013)
              Therapeutics must diffuse through the brain extracellular space (ECS) in order to distribute within the central nervous system (CNS) compartment; this requirement holds both for drugs that are directly placed within the CNS (i.e., central input) and for drugs that cross the barriers separating blood and brain following systemic administration. The diffusion of any substance within the CNS may be affected by a number of properties associated with the brain microenvironment, e.g., the volume fraction, geometry, width, and local viscosity of the ECS, as well as interactions with cell surfaces, the extracellular matrix, and components of the interstitial fluid. Here, we discuss ECS properties important in governing the distribution of macromolecules (e.g., antibodies and other protein therapeutics), nanoparticles and viral vectors within the CNS. We also provide an introduction to some of the methods commonly applied to measure diffusion of molecules in the brain ECS, with a particular emphasis on those used for determining the diffusion properties of macromolecules. Finally, we discuss how quantitative diffusion measurements can be used to better understand and potentially even improve upon CNS drug delivery by modeling delivery within and across species, screening drugs and drug conjugates, evaluating methods for altering drug distribution, and appreciating important changes in drug distribution that may occur with CNS disease or injury.
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                Author and article information

                Contributors
                Elena Belova: +1.617.674.7173 , elena.belova@pfizer.com
                Bio :
                Dr. Elena Belova

                is a Senior Scientist in the Modeling and Simulation Group within the Department of Pharmacokinetics, Dynamics, and Metabolism at Pfizer, and her focus is a modeling support of the neuroscience/pain research programs.

                Christopher L. Shaffer:
                Bio :
                Dr. Christopher Shaffer

                holds a BS in chemistry (high honors) from The College of William & Mary and a M.S. and Ph.D. (honors) in medicinal chemistry from the University of Kansas. Immediately following graduate school, Chris joined the Department of Pharmacokinetics, Dynamics, and Metabolism (PDM) as a biotransformation lab head working on CNS projects from preclinical development through POC. Four years later, Chris became a PDM lab head in CNS Discovery, where he worked for 9 years. In addition to PDM project representative roles on numerous CNS projects, Chris was the Research Project Leader for a number of programs. In August 2014, Chris formally joined the Neuroscience & Pain Research Unit (NPRU) as a Portfolio Lead within the NeuroOpportunities Group. Chris has led many neuroscience-centric interdisciplinary efforts such as translational neuropharmacology and accurately projecting the human pharmacokinetics and neuropharmacokinetics of small molecules to optimize their clinical dosing regimens. Chris has co-authored 40 peer-reviewed manuscripts, speaks regularly in diverse external forums, and is a member of the American Chemical Society and its Medicinal Chemistry Division as well as the Society for Neuroscience.

                Patrick E. Trapa:
                Bio :
                Dr. Patrick Trapa

                leads the neuroscience/pain quantitative translation group within the Department of Pharmacokinetics, Dynamics, and Metabolism at Pfizer. His team is primarily responsible for supporting projects from early discovery through candidate selection. Patrick received his bachelor’s and Ph.D. from MIT in Materials Science and Engineering and an M.B.A. from the University of Rhode Island. After completing his doctoral work, he co-founded a lithium-polymer-battery company and later served as lecturer and research associate at MIT. During this time, he also consulted with NASA on high-temperature metallurgy projects. He then ran the specialty battery division at a publicly traded battery company before entering Pfizer in 2006. Patrick has held roles in preformulations as well as ADME, PK/PD, and systems modeling. He presently leads several PBPK efforts in addition to actively supporting the neuroscience/pain portfolio.

                Journal
                Journal ID (nlm-ta): Med Biol Eng Comput
                Journal ID (iso-abbrev): Med Biol Eng Comput
                Title: Medical & Biological Engineering & Computing
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0140-0118
                ISSN (Electronic): 1741-0444
                Publication date (Electronic): 11 May 2017
                Publication date PMC-release: 11 May 2017
                Publication date (Print): 2017
                Volume: 55
                Issue: 12
                Pages: 2069-2077
                Affiliations
                ISNI 0000 0000 8800 7493, GRID grid.410513.2, Worldwide Research & Development, , Pfizer Inc., ; 1 Portland Street, Cambridge, MA 02139 USA
                Article
                Publisher ID: 1650
                DOI: 10.1007/s11517-017-1650-x
                PMC ID: 5680405
                PubMed ID: 28493093
                SO-VID: 35cd4011-3535-43dc-83fd-f5b73e4e6ff0
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 22 September 2016
                Date accepted : 18 April 2017
                Categories
                Subject: Original Article
                Custom metadata
                issue-copyright-statement © International Federation for Medical and Biological Engineering 2017

                ScienceOpen disciplines: Biomedical engineering
                Keywords: convection-enhanced delivery (ced),central nervous system (cns),neurotrophic factor,intraparenchymal infusion,computational model
                Data availability:
                ScienceOpen disciplines: Biomedical engineering
                Keywords: convection-enhanced delivery (ced), central nervous system (cns), neurotrophic factor, intraparenchymal infusion, computational model

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