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
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 • Degenerative neurological diseases - Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, etc • Cancers of the CNS CNS Diseases & Disorders
Blood-Brain Barrier (BBB) & Blood-CSF Barrier (BCSFB) Specialized Barriers - BBB
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
Schematic Representation of the Blood-CSF Barrier Deeken J F , Löscher W Clin Cancer Res 2007;13:1663-1674.
Drug Transporters in BBB Deeken J F , Löscher W Clin Cancer Res 2007;13:1663-1674
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
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)
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
Biophase Analysis for PK Studies Alavijeh M.S. et al. J. Americ. Exp. Ther. 2005, 2:554-71.
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.
In Vivo Microdialysis Zapata A et al. Curr. Protocols in Neurosci. 2009.
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
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
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
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)
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
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
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)