EXTH-02. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF 5-AZACYTIDINE ALONE AND IN COMBINATION WITH INULIN IN A NON-HUMAN PRIMATE MODEL

To evaluate the CNS exposure of 5-azacytidine (5-AZA) plasma and CSF pharmacokinetics (PK) and cortical extracellular fluid (ECF) concentrations, via microdialysis (MD), were studied in a nonhuman primate model (NHP) following intravenous (IV), intranasal (IN), intraventricular (IT-V), intralumbar (IT-L) administration. 5-AZA was administered to 8 rhesus macaques; IV (3.75 mg/kg), IN (20 mg), IT (10 mg). 5-AZA with Inulin was administered IT-V (5-AZA-10mg/Inulin-2mg) to examine IT clearance. Cortical ECF, plasma, CSF, and tissue were collected. 5-AZA levels were quantified via an uHPLC-MS/MS assay and PK parameters calculated using non-compartmental methods. Mean Data. IV: Plasma AUC0-∞ 2.93 hr*uM and Clearance (CL) 107.2 L/hr/m2. IN: Plasma AUC0-∞ 0 hr*uM 5-AZA CSF concentrations were not quantifiable for IV or IN administration. IT-V: Plasma: AUC0-∞ 0.29 hr*uM and CL 353.4 L/hr/m2 CSF: AUC0-∞ 2902.9 hr*uM and CL 0.308 ml/min IT-L: Plasma: AUC0-∞ 0.46 hr*uM and CL 222.9 L/hr/m2 CSF: AUC0-∞ 12.8 hr*uM and CL 61.91 ml/min Inulin IT-V: Plasma: AUC0-∞ 11.84 hr*uM and CL 1.6 L/hr/m2 CSF: AUC0-∞ 7874.5 hr*uM and CL 0.018 ml/min. Inulin (w/5-AZA) IT-V: Plasma: AUC0-∞ 0 hr*uM CSF: AUC0-∞ 7752.5 hr*uM, and CL 0.018 ml/min 5-AZA (w/Inulin) IT-V: Plasma: AUC0-∞ 0 hr*uM CSF: AUC0-∞ 1976.6 hr*uM and CL 0.410 ml/min MD/PK IT-V: Plasma: AUC0-∞ 0.158 hr*uM and CL 391.6 L/hr/m2 CSF: 583.9 AUC0-∞ hr*uM and CL 2.36 ml/min. 5-AZA concentrations were not quantifiable for ECF. Tissue: Percentage of total dose recovered in tissue: Brain 1.7% distributed as Cortex 71%, Pons 4%, Medulla 5%, Cerebellum 20%. 0% recovered in liver and kidney. IT administration is necessary to achieve significant 5-AZA exposure in the CSF. 5-AZA clearance is not equivalent across the CSF space and is greater than bulk flow. Following IT delivery, 5-AZA does not remain in the ECF but is swiftly incorporated into brain tissue.