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Research ArticleDrug Discovery and Translational Medicine

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

Fernando Carreño, Victória Eteges Helfer, Keli Jaqueline Staudt, Laura Bem Olivo, Karina Paese, Fabíola Schons Meyer, Ana Paula Herrmann, Sílvia Stanisçuaski Guterres, Stela Mari Kuze Rates, Iñaki Trocóniz and Teresa Dalla Costa
Journal of Pharmacology and Experimental Therapeutics October 2020, 375 (1) 49-58; DOI: https://doi.org/10.1124/jpet.120.000109
Fernando Carreño
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Victória Eteges Helfer
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Keli Jaqueline Staudt
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Laura Bem Olivo
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Karina Paese
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Fabíola Schons Meyer
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Ana Paula Herrmann
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Sílvia Stanisçuaski Guterres
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Stela Mari Kuze Rates
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Iñaki Trocóniz
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Teresa Dalla Costa
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)
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Abstract

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 bolus 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 (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 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.

Footnotes

    • Received May 15, 2020.
    • Accepted July 14, 2020.
  • This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil) [Grant 421767/2016-2] and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Brazil (CAPES) [Finance Code 001].

  • The authors declare no conflict of interest.

  • https://doi.org/10.1124/jpet.120.000109.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 1
1 Oct 2020
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Research ArticleDrug Discovery and Translational Medicine

PopPK Modeling of QLNC in an Animal Model of Schizophrenia

Fernando Carreño, Victória Eteges Helfer, Keli Jaqueline Staudt, Laura Bem Olivo, Karina Paese, Fabíola Schons Meyer, Ana Paula Herrmann, Sílvia Stanisçuaski Guterres, Stela Mari Kuze Rates, Iñaki Trocóniz and Teresa Dalla Costa
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 49-58; DOI: https://doi.org/10.1124/jpet.120.000109

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Research ArticleDrug Discovery and Translational Medicine

PopPK Modeling of QLNC in an Animal Model of Schizophrenia

Fernando Carreño, Victória Eteges Helfer, Keli Jaqueline Staudt, Laura Bem Olivo, Karina Paese, Fabíola Schons Meyer, Ana Paula Herrmann, Sílvia Stanisçuaski Guterres, Stela Mari Kuze Rates, Iñaki Trocóniz and Teresa Dalla Costa
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 49-58; DOI: https://doi.org/10.1124/jpet.120.000109
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