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

Autor: Funguetto-Ribeiro AC; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, 97500-970, Brazil., Maciel TR; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, 97500-970, Brazil., Lunardi AG; Curso de Farmácia, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, Brazil., Gomes DB; Curso de Farmácia, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, Brazil., Ibarra M; Departamento de Ciencias Farmacéuticas, Facultad de Química - Universidad de la República, UDELAR, Avenida General Flores 2124, P.O. Box 1157, 11800, Montevideo, Uruguay. mibarra@fq.edu.uy., Haas SE; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, 97500-970, Brazil. sandrahaas@unipampa.edu.br.; Curso de Farmácia, Universidade Federal do Pampa, UNIPAMPA, BR 472, Km 592, Uruguaiana, RS, Brazil. sandrahaas@unipampa.edu.br.
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2023 Jul; Vol. 40 (7), pp. 1751-1763. Date of Electronic Publication: 2023 Jun 22.
DOI: 10.1007/s11095-023-03551-8
Abstrakt: 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 (MonolixSuite TM -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 IC 50 , 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.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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