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Review
. 2018 Jul 3:8:239.
doi: 10.3389/fonc.2018.00239. eCollection 2018.

Beyond the Blood:Brain Barrier: The Importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, Including Diffuse Intrinsic Pontine Glioma

Katherine Elizabeth Warren  1
Affiliations
Review

Beyond the Blood:Brain Barrier: The Importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, Including Diffuse Intrinsic Pontine Glioma

Katherine Elizabeth Warren. Front Oncol. .

Abstract

Over the past decade, we have made considerable progress in establishing diffuse intrinsic pontine glioma (DIPG) as a disease entity and developing preclinical tools to interrogate potential therapeutics. However, translation to improved clinical outcomes in children with DIPG has not yet been realized. This is in part due to difficulties encountered in delivering active drugs adequately to the tumor site. However, most preclinical evaluations gloss over the fundamental concepts of central nervous system (CNS) pharmacokinetics and requirements needed to optimize drug delivery and exposure and translate this into efficacious therapy. This article discusses not only the blood:brain barriers but additional barriers to drug delivery for CNS tumors and pharmacokinetic principles that need to be addressed and considered.

Keywords: blood:brain barrier; brain tumor; central nervous system pharmacokinetics; diffuse intrinsic pontine glioma; drug delivery.

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Figures

Figure 1
Figure 1
Schematic of blood:brain barrier (BBB), brain parenchyma, and stroma. Small, unbound, lipophilic agents are able to cross the BBB. They then must cross through brain parenchyma by diffusion across the extracellular space to reach tumor cells (image by Katie Allen).
Figure 2
Figure 2
(A) Illustration of microdialysis setup. Drug of interest (TMZ) was administered systemically. (B) Concentration versus time curves of temozolomide measured in plasma, cerebrospinal fluid (CSF), cortex ECF, and pontine ECF (courtesy of Cindy McCully).
Figure 3
Figure 3
Magnetic resonance imaging demonstrating (A) non-enhancing tumor at diagnosis (left) and enhancement (right) following radiation therapy; (B) tumor necrosis (enhancement at diagnosis, left) and FLAIR image (right) showing extent of tumor beyond area of enhancement, and (C) intratumoral cysts. Areas of contrast enhancement do not represent tumor burden in diffuse intrinsic pontine glioma and do not ensure adequate drug delivery.
See this image and copyright information in PMC

References

    1. Castel D, Philippe C, Calmon R, Le Dret L, Truffaux N, Boddaert N, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol (2015) 130(6):815–27.10.1007/s00401-015-1478-0 - DOI - PMC - PubMed
    1. Zhang Y, Dong W, Zhu J, Wang L, Wu X, Shan H. Combination of EZH2 inhibitor and BET inhibitor for treatment of diffuse intrinsic pontine glioma. Cell Biosci (2017) 7:56.10.1186/s13578-017-0184-0 - DOI - PMC - PubMed
    1. Kerr JZ, Berg SL, Dauser R, Nuchtern J, Egorin MJ, McGuffey L, et al. Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates. Cancer Chemother Pharmacol (2001) 47(5):411–4.10.1007/s002800000253 - DOI - PubMed
    1. Veldhuijzen van Zanten SEM, El-Khouly FE, Jansen MHA, Bakker DP, Sanchez Aliaga E, Haasbeek CJA, et al. A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol (2017) 135(2):307–15.10.1007/s11060-017-2575-9 - DOI - PMC - PubMed
    1. Becher OJ, Millard NE, Modak S, Kushner BH, Haque S, Spasojevic I, et al. A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors. PLoS One (2017) 12(6):e0178593.10.1371/journal.pone.0178593 - DOI - PMC - PubMed