PT-023 - DEVELOPMENT OF INTRANASAL PHYSIOLOGICALLY BASED NOSE TO BRAIN MODEL AND ITS APPLICATION TO CHARACTERIZE IN NEUROEPO ABSORPTION VIA NASAL ROUTE AND DISTRIBUTION TO LUMBAR CSF IN HEALTHY NON-HUMAN PRIMATES (CYANOMOLGUS MONKEY).

P. Mehta¹, A. Brito Llera², H. Colom Codina³, L. Rodriguez Vera¹, I. Maria Sosa Teste⁴, D. Jay Perez⁴, T. de Jesus Rodriguez Obaya⁴, V. Vozmediano¹; ¹University of Florida, Gainesville, FL, USA, ²University of Havana, Havana, Cuba, ³University of Barcelona, Barcelona, Spain, ⁴CETEX, National Center for the Production of Laboratory Animals, Havana, Cuba.

Background: One of the biggest challenges to treat neurological disorders is to deliver the drug across the blood brain barrier (BBB). To overcome this challenge NeuroEPO, a nasal solution of non-hematopoietic recombinant human erythropoietin (EPO) with low sialic acid was developed. NeuroEPO has shown promise as a neuroprotective against Parkinson’s Disease.

Methods: We proposed a novel intranasal physiologically based nose to brain (PBNB) model. Literature data was collected to account for the physiological parameters of the monkey brain. To characterize the endogenous production of EPO in CNS and kidney, the physiological synthesis was incorporated in the PBNB and used to initialized the model compartments . The final PBNB model was built in Pumas version 2.1.

Results: The PBNB model consists of the middle turbinate, and olfactory cells (absorption compartment) linked to four brain compartments (Brain blood, Brain mass, Cranial CSF, Lumbar CSF) and integrates the endogenous turnover in brain and plasma. Injection volume was included as a model input. The PBNB model was able to appropriately describe the absorption and distribution of NeuroEPO in the Lumbar CSF. The PBNB model predictions were compared with 1) Observed NeuroEPO Lumbar CSF concentrations and 2) Observed NeuroEPO plasma concentrations. The model predictions were able to capture the observed data within the 95% CI.

Conclusion: The PBNB model can help to better understand the nose-to-brain access and inform the clinical development of NeuroEPO. Future steps include the exploration of potential active mechanisms involve in the CNS access, the link to pharmacodynamic mechanisms from quantitative electroencephalograms and the scaling to predict the human CNS concentrations.