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Clozapine-loaded nanocapsules improve antipsychotic activity in rats: building a sequential PopPK/PD model to discriminate nanocarriers in the preformulation step

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Abstract

Purpose

We investigated the impact of nanoformulations on the dose-exposure-response relationship of clozapine (CZP), a low-solubility antipsychotic with serious adverse effects, using a popPK/PD approach.

Methods

We evaluated the pharmacokinetics and PK/PD profiles of three coated polymeric CZP-loaded nanocapsules functionalized with polysorbate 80 (NCP80), polyethylene glycol (NCPEG), and chitosan (NCCS). Data on in vitro CZP release by dialysis bag, plasma pharmacokinetic profiles in male Wistar rats (n = 7/group, 5 mg kg-1, i.v.), and percentage of head movements in a stereotyped model (n = 7/group, 5 mg kg-1, i.p.) were integrated using a sequential model building approach (MonolixSuiteTM-2020R1-Simulation Plus).

Results

A base popPK model developed with CZP solution data collected after the i.v. administration of CZP was expanded to describe the changes in drug distribution caused by nanoencapsulation. Two additional compartments were inserted into the NCP80 and NCPEG models, and a third compartment was included in the NCCS model. The nanoencapsulation showed a decrease in the central volume of distribution for NCCS (V1NCpop = 0.21 mL), while for FCZP, NCP80, and NCPEG, it was ~1 mL. The peripheral distribution volume was higher for the nanoencapsulated groups (19.1 and 129.45 mL for NCCS and NCP80, respectively) than for FCZP. The popPK/PD model showed a formulation-dependent plasma IC50, with 20-, 50-, and 80-fold reductions compared to the CZP solution (NCP80, NCPEG, and NCCS, respectively).

Conclusion

Our model discriminates the coatings and describes the peculiar PK and PD behavior of nanoencapsulated CZP, especially NCCS, making it an exciting tool for evaluating the preclinical performance of nanoparticles.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgments

This study was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES). The authors are grateful for the support provided by the Rio Grande do Sul Science Foundation (FAPERGS), grant 19/2551-0001970-0, National Counsel of Technological and Scientific Development (CNPq) (#309401/2020-8), CAPES (#88881.506652/2020-01), UNIPAMPA, and UDELAR. S.E. Haas is the recipient of a CNPq fellowship. We would also like to thank Atlas Assessoria Linguística for language editing.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, 97500-970, Brazil

    Ana Cláudia Funguetto-Ribeiro, Tamara Ramos Maciel & Sandra Elisa Haas

  2. Curso de Farmácia, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, Brazil

    Annelize Gruppi Lunardi, Daniel Borges Gomes & Sandra Elisa Haas

  3. Departamento de Ciencias Farmacéuticas, Facultad de Química – Universidad de la República, UDELAR, Avenida General Flores 2124, P.O. Box 1157, 11800, Montevideo, Uruguay

    Manuel Ibarra

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  1. Ana Cláudia Funguetto-Ribeiro
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Contributions

Ana Cláudia Funguetto Ribeiro: Conceptualization, Investigation, Writing - Review & Editing. Tamara Ramos Maciel: Methodology, Investigation. Annelize Gruppi Lunnardi: Methodology, Investigation. Daniel Gomes Borges: Methodology, Investigation. Manuel Ibarra: Project administration, Formal analysis, Writing – Review & Editing. Sandra Elisa Haas: Conceptualization, Project administration, Funding acquisition, Writing - Review & Editing.

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Funguetto-Ribeiro, A.C., Maciel, T.R., Lunardi, A.G. et al. Clozapine-loaded nanocapsules improve antipsychotic activity in rats: building a sequential PopPK/PD model to discriminate nanocarriers in the preformulation step. Pharm Res 40, 1751–1763 (2023). https://doi.org/10.1007/s11095-023-03551-8

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