Semi-Mechanistic Pharmacokinetic Modeling of Lipid Core Nanocapsules: Understanding Quetiapine Plasma and Brain Disposition in a Neurodevelopmental Animal Model of Schizophrenia

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 375; no. 1; pp. 49 - 58
• Main Authors: Carreño, Fernando, Helfer, Victória Eteges, Staudt, Keli Jaqueline, Olivo, Laura Bem, Paese, Karina, Meyer, Fabíola Schons, Herrmann, Ana Paula, Guterres, Sílvia Stanisçuaski, Kuze Rates, Stela Mari, Trocóniz, Iñaki, Dalla Costa, Teresa
• Format: Journal Article
• Language: English
• Published: United States 01.10.2020
• Subjects: Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - pharmacology; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Drug Carriers - administration & dosage; Drug Carriers - pharmacokinetics; Female; Male; Microdialysis; Models, Biological; Nanocapsules - administration & dosage; Quetiapine Fumarate - administration & dosage; Quetiapine Fumarate - blood; Quetiapine Fumarate - pharmacokinetics; Quetiapine Fumarate - pharmacology; Rats; Rats, Wistar; Reflex, Startle - drug effects; Schizophrenia - blood; Schizophrenia - drug therapy; Schizophrenia - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/JPET.120.000109

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naive and schizophrenic (SCZ-like) rats and developed a semimechanistic model to describe changes in both compartments following administration of the drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/ml) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0% ± 1.4%). A model was built using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single intravenous dose of FQ or QLNC to naive and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bidirectional drug transport across the blood-brain barrier (CL and CL ). SCZ-like rats' significant decrease in brain exposure with FQ (decrease in CL ) was reverted by QLNC, showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LNC 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 the drug's brain distribution following administration of both free drug in solution or as nanoformulation to naive 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.