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

Abstract

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 ± 39 nm, low polydispersity, and high encapsulation (93.0 ± 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 (CL in and CL out ). SCZ-like rats significant decrease in brain exposure with FQ (decrease in CL in ) was reverted by QLNC showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LCN for brain delivery. SIGNIFICANCE STATEMENTA 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.

Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats

“…The biggest limitation of this work is related to SCZ, which is a very complex disease and difficult to mimic in an animal model, although the animal model used presents face, predictive, and construct validity 27,28 . It is also important to point out that DA concentrations were investigated only in mPFC, which is not the brain region where the QTP effect is more pronounced, 29 although previous work from our group has demonstrated that QTP levels in the hippocampus and mPFC did not differ after FQ and QLNC administration 19 . From a translational point of view, the current contribution untangles drug effects into disease status, PK, and PD, allowing an in silico investigation integrating human PK and drug PD properties.…”

“… 27 , 28 It is also important to point out that DA concentrations were investigated only in mPFC, which is not the brain region where the QTP effect is more pronounced, 29 although previous work from our group has demonstrated that QTP levels in the hippocampus and mPFC did not differ after FQ and QLNC administration. 19 From a translational point of view, the current contribution untangles drug effects into disease status, PK, and PD, allowing an in silico investigation integrating human PK and drug PD properties. Also, we highlight the importance in evaluating PK and PD in a disease animal model.…”

“…Typical unbound brain QTP concentration profiles for each experimental group were generated from the semimechanistic PK model developed previously 19 (Figure S2 ) and were used as the drivers of the DA response.…”