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Published on: April 16, 2019
Evaluating "brain permeability": A critical issue for the development of therapeutic agents for primary and
Stuart A Grossman1, Amy Barone1, Roy E Strowd1
1Department of Oncology, Johns Hopkins University (S.A.G., R.R., C.H., K.C.S., C.R., J.O.B., D.O.K., P.S., T.P.); Food and Drug Administration (FDA), Silver Spring, Maryland, USA (A.B., E.D., E.W., L.S.L.P., T.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA (W.F.E.); Wake Forest School of Medicine, Winston-Salem, North Carolina, USA (R.E.S., G.L.); Department of Neurosurgery, Barrow's Neurologic Institute, Phoenix, Arizona, USA (N.S.); Medical Oncology, City of Hope, Duarte, California, USA (J.P.); Department of Neurology, University of Alabama Birmingham, Birmingham, Alabama, USA (B.N.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA (J.N.S.); Department of Medicine, Cleveland Clinic, Cleveland, Ohio, USA (D.P.); Department of Neurology, University of Virginia, Charlottesville, Virginia, USA (D.S.).
Abstract:
Current assessments of brain permeability rely predominantly on drug delivery to contrast-enhancing tumor regions. However, substantial portions of central nervous system (CNS) tumors reside within non-enhancing brain (NEB), where drug concentrations frequently remain subtherapeutic. This collaborative Adult Brain Tumor Consortium and Food and Drug Administration workshop aimed to identify criteria for defining NEB permeability to accomplish 2 critical objectives: (1) allocate clinical trial resources toward agents achieving therapeutic NEB concentrations and (2) minimize systemic toxicity when CNS benefit is improbable. The workshop systematically evaluated permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain. Methodological approaches to determine requisite NEB drug concentrations and approaches to measuring NEB pharmacokinetics and pharmacodynamics were examined. This culminated in developing the Non-Enhancing Brain Permeability Index (NEBPI), which assigns therapeutic agents to 3 categories: sufficiently permeable, insufficiently permeable, or impermeable. The NEBPI provides a standardized framework to assist investigators and regulatory agencies to evaluate NEB penetration before human efficacy studies are initiated for agents that require direct tumor contact. Assessing NEB drug penetration is critical to improving outcomes in CNS tumors and reducing the incidence of brain metastases in systemic malignancies.
Insights
New criteria assess drug penetration into non-enhancing brain tumors (NEB). The Non-Enhancing Brain Permeability Index (NEBPI) helps select effective CNS agents and reduce toxicity.
Area of Science:
- Neuro-oncology
- Pharmacology
- Drug Delivery
Background:
- Current brain tumor drug delivery assessments often overlook non-enhancing brain (NEB) regions, where drug concentrations are frequently subtherapeutic.
- This limitation hinders the development of effective treatments for substantial portions of central nervous system (CNS) tumors.
Purpose of the Study:
- To establish criteria for defining NEB permeability for CNS tumor agents.
- To guide clinical trial resource allocation towards agents with therapeutic NEB concentrations.
- To minimize systemic toxicity by identifying agents unlikely to benefit CNS tumors.
Main Methods:
- Systematic evaluation of permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain.
- Examination of methods to determine requisite NEB drug concentrations and measure NEB pharmacokinetics and pharmacodynamics.
Main Results:
- Development of the Non-Enhancing Brain Permeability Index (NEBPI).
- The NEBPI categorizes therapeutic agents into three levels: sufficiently permeable, insufficiently permeable, or impermeable.
- Provides a standardized framework for evaluating NEB penetration.
Conclusions:
- The NEBPI offers a standardized approach for evaluating drug penetration into NEB regions before human efficacy studies.
- Accurate assessment of NEB drug penetration is crucial for improving CNS tumor outcomes and reducing brain metastases.
- This framework aids investigators and regulatory agencies in optimizing drug development for CNS malignancies.
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