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Cited by 68Drug Transport and Resistance MechanismsBarrier Structure and Function StudiesGlioma Diagnosis and Treatment

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Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood–Brain Barrier in Glioblastoma Patients Using an IVIVE–PBPK Modeling Approach

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Li, Jing, Wu, Jianmei, Bao, Xun, Honea, Norissa, Xie, Youming, Kim, Seongho, Sparreboom, Alex, Sanai, Nader·2017·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-17-0983PMC PMC6097184

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Abstract

Abstract Purpose: AZD1775, a first-in-class, small-molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radiosensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across the human blood–brain barrier (BBB). Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 patients with glioblastoma. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a four-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results: AZD1775 exhibited good tumor penetration in patients with glioblastoma, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII–ABCB1 or MDCKII–ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant, driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Clin Cancer Res; 23(24); 7454–66. ©2017 AACR. See related commentary by Peer et al., p. 7437

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  • IVIVE is more physiologically relevant than AS because it incorporates physiological factors and includes the possibility to expand with mechanistic models.

    “it is more physiologically relevant than AS, considering that IVIVE incorporates physiological factors and includes the possibility to expand with the mechanistic model [8,9].”

    From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [9]

    The Introduction (page not provided) describes IVIVE–PBPK modeling as integrating drug-specific and physiological, system-specific parameters into a mechanistic model. The paper does not compare it with AS or establish that it is more physiologically relevant than AS. (LLM, conf=0.84)

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Metadata

Authors
Li, J., Wu, J., Bao, X., Honea, N., Xie, Y., Kim, S., Sparreboom, A., & Sanai, N.
Affiliations
  • Wayne State University (US)
  • Barrow Neurological Institute (US)
  • The Ohio State University (US)
Corresponding author
  • Li, Jing
  • Sanai, Nader
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2017-12-14
Volume
23
Issue
24
Pages
7454-7466
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-17-0983
PMC
PMC6097184
OpenAlex
W2754610420
Cited by
68
References
0
Citations by year
2026: 11 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 13 · 2020: 6 · 2019: 6 · 2018: 2 · 2017: 1
FWCI
1.81
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
United States Public Health Service (P30 CA022453)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Keywords
AZD1775, glioblastoma, blood-brain barrier penetration, Wee1 kinase inhibitor, P-glycoprotein, ABCG2, OATP1A2, efflux pumps, tumor microenvironment pH, physiologically based pharmacokinetic modeling
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 2, Adult, Aged, Aged, 80 and over, Animals, Biological Transport, Blood-Brain Barrier, Dogs, Glioblastoma, Humans, Middle Aged, Neoplasm Proteins, Nuclear Proteins, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Pyrimidinones, Gene Expression Regulation, Neoplastic, ATP Binding Cassette Transporter, Subfamily B, Cell Cycle Proteins, Organic Anion Transporters, Tumor Microenvironment, Madin Darby Canine Kidney Cells

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