SEMI-MECHANISTIC PHARMACOKINETIC MODELING OF LIPID CORE NANOCAPSULES: UNDERSTANDING QUETIAPINE PLASMA AND BRAIN DISPOSITION IN A NEURODEVELOPMENTAL ANIMAL MODEL OF SCHIZOPHRENIA.

Carreño, Fernando; Helfer, Victória E; Staudt, Keli J; Olivo, Laura B; Paese, Karina; Meyer, Fabíola S; Herrmann, Ana P; Guterres, Sílvia S; Rates, Stela Maris Kuze; Trocóniz, Iñaki F; Dalla Costa, Teresa

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naïve and schizophrenic (SCZ-like) rats and developed a semi-mechanistic model to describe changes in both compartments following administration of drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/mL) presented 166 {plus minus} 39 nm, low polydispersity, and high encapsulation (93.0 {plus minus} 1.4%). Model building using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single i.v. bolus dose of FQ or QLNC to naïve and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bi-directional drug transport across the blood-brain barrier (CLin and CLout). SCZ-like rats significant decrease in brain exposure with FQ (decrease in CLin) was reverted by QLNC showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LCN for brain delivery. Significance Statement A population approach was used to simultaneously model total and unbound plasma and unbound brain quetiapine concentrations allowing for quantification of the rate and extent of drug's brain distribution following administration of both free drug in solution or as nanoformulation to naïve and SCZ-like rats. The model-based approach is useful to better understand the possibilities and limitations of this nanoformulation for drug delivering to the brain, opening the opportunity to use this approach to improve SCZ-treatment limited response rates.