Modelagem farmacocinética/farmacodinâmica populacional de clozapina nanoencapsulada em ratos Wistar

Abstract

Clozapine (CZP) is an atypical antipsychotic prescribed in cases of refractory schizophrenia due to serious adverse effects associated with its use. Variable pharmacokinetics are also observed, caused by extensive pre-systemic metabolism, resulting in bioavailability ranging from 27 to 47%. Nanotechnology comes as a promising delivery strategy in order to improve brain exposure to drugs that act on the central nervous system. The aim of the present study was to describe the dose-exposure-response relationship of male Wistar rats treated with free or nanoencapsulated CZP solution with polysorbate 80 (NCCZP), polyethylene glycol (NCCZP-PEG) or chitosan (NCCZP-CS), using an sequential population pharmacokinetic/pharmacodynamic (popPK/PD) approach. Data were collected from a previous study by Vieira et al. (2016). The Monolix® - Lixoft software was used for data modeling. First, population pharmacokinetic modeling (popPK) of the free CZP group was defined and new compartments were incorporated in order to represent the distribution of NCCZP, NCCZP-PEG and NCCZP-CS. The popPK data were fixed and the pharmacodynamic parameters (popPD) were estimated. A two-compartment model, associated with the proposed model for free CZP, adequately described the behavior for NCCZP and NCCZP-PEG. While NCCZP-CS was best described by a three-compartment model, associated with the model proposed for free CZP. The results showed that nanoencapsulation increased the distribution for all groups, being higher for NCCZP-PEG. From the sequential popPK/PD, a reduction in the amount of drug needed to obtain 50% of the maximum response (IC50) was observed for all groups. Together NCCZP, NCCZP-PEG and NCCZP-CS have been shown to be more potent and therapeutically promising in pharmacological therapy for patients with schizophrenia.