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Special Issues in Development of CNS Active Drugs. Nimita Dave, Ph.D. 04/03/13. Barriers/Challenges Examples Techniques to Study Brain Pharmacokinetics Brain Tumors Our Findings (Letrozole). Outline. Brain injury CNS Infections Epilepsy

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Special Issues in Development of CNS Active Drugs


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    1. Special Issues in Development of CNS Active Drugs Nimita Dave, Ph.D. 04/03/13

    2. Barriers/Challenges • Examples • Techniques to Study Brain Pharmacokinetics • Brain Tumors • Our Findings (Letrozole) Outline

    3. Brain injury • CNS Infections • Epilepsy • Degenerative neurological diseases - Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, etc • Cancers of the CNS CNS Diseases & Disorders

    4. Blood-Brain Barrier (BBB) & Blood-CSF Barrier (BCSFB) Specialized Barriers - BBB

    5. Schematic Comparison of a Brain Capillary (B) with a Capillary in the Periphery (A) Deeken J F , Löscher W Clin Cancer Res 2007;13:1663-1674

    6. Schematic Representation of the Blood-CSF Barrier Deeken J F , Löscher W Clin Cancer Res 2007;13:1663-1674.

    7. Transport Across BBB

    8. Drug Transporters in BBB Deeken J F , Löscher W Clin Cancer Res 2007;13:1663-1674

    9. MW < 450; preferably <400 • <6 H-bond acceptors; <2 H-bond donors • Neutral or basic (pKa 7.5-10.5) • Polar surface area <90 A • Log D between 1 and 3 • Low affinity to efflux mechanisms Physicochemical Properties of a Successful CNS Drug

    10. Barbiturates

    11. Benzodiazepines

    12. Methods for Determining BBB Permeability (Rate) – • - In silico (eg. RO-4) • - Cell-based (MDCK-MDR1) • Brain uptake index • Pgp KO mice • Methods for Determining BBB Penetration (Extent) – • - Total Brain (B:P) • - CSF • Microdialysis Techniques Available for Brain PK/PD Studies • Methods for Determining Concentration Relevant to • Pharmacology (Extent & Relevance) – • Receptor occupancy • Biological Efficacy (eg. CNS Biomarkers)

    13. Tissue sampling – Invasive, Only 1 or 2 samples • Imaging – Non-invasive but costly, inefficient • Microdialysis – Invasive, Repeat measures over time, sampling of ECF Techniques available for Brain PK Studies

    14. Biophase Analysis for PK Studies Alavijeh M.S. et al. J. Americ. Exp. Ther. 2005, 2:554-71.

    15. Continuous sampling in the ECF • Relatively cost efficient • Reliable for PK evaluation of drugs in brain and brain tumors • Facilitate comparison to plasma PK Intracerebral Microdialysis Müller M BMJ 2002;324:588-591.

    16. In Vivo Microdialysis Zapata A et al. Curr. Protocols in Neurosci. 2009.

    17. Near real-time measurement of unbound drug near site of action in the brain • Simultaneous measurement of drug PK in brain and plasma, contributed to decreased inter-subject variability • Serial sample collections done while subjects/animals are awake • More thank one cannula can be places at one time, enabling concurrent mesaurements in multiple regions • No extractions required for bioanalysis Advantages

    18. Invasive technique • Cannula/Catheter calibration is needed to estimate the true drug concentration in tissue • Sensitive analytical methods are needed tp detect drug concentrations in the dialysate samples • In vitro testing required to determine if the drug of interest is a candidate for microdialysis Disadvantages

    19. Primary Tumors OR Metastatic Tumors • More common • Occur in 20-40% of cancer patients • Most common occurrence in lung & • breast malignancies 1. Gliomas 2. Meningiomas 3. Schwannomas 4. Medulloblastomas 80% of malignant tumors a. Astrocytoma b. Oligodendroglioma c. Ependymoma Grade I - Pilocytic Brain Carcinomas Grade II – Diffuse Grade III – Anaplastic/Malignant Grade IV – Glioblastoma multiforme

    20. 5-year survival rates are third-lowest among all cancers • Second leading cause of death in children and men • Fifth leading cause of death in women • 69,720 new cases of primary brain tumors and more than 100,000 cases of metastatic brain tumors are estimated in 2013 Global Incidence of Brain Tumors Central Brain Tumor Registry of the United States (CBTRUS); American Brain Tumor Association (ABTA)

    21. Surgery – Craniotomy/Stereotactic surgery/Image-guided surgery (IGS) 2. Radiation Therapy – Whole Brain Radiotherapy (WBRT)/Steroetactic radiosurgery Treatment of Brain Tumors 3. Chemotherapy – Very few efficacious agents

    22. The incidence of CNS tumors is on the rise due to several reasons. • Treatment modalities limited by potential adverse effects • Tumor heterogeneity - population of rapidly dividing and non-dividing cells, variable regions of hypoxia, perfusion, neo-angiogenesis, infiltrating cancer cells • Intrinsic and acquired drug resistance • Lack of selectivity for tumor cells • Overcoming the CNS sanctuary formed by the Blood Brain Barrier (BBB) represents a critical challenge to the cancer researchers Barriers/Challenges to the Treatment of Brain Tumors

    23. An abnormal barrier consisting of vesicles, open junctions, and fragmented basal lamina exists in brain tumor vasculature and is termed BTB (Greig, 1987) • Tumors produce angiostimulating factors that cause increased vascular proliferation • Enhanced permeability of BTB compared to BBB Blood-Tumor Barrier (BTB)