PK/PD modelling of the effect of nanoencapsulated quetiapine on cortical dopamine concentrations in schizophrenia phenotyped rats
Bruna Bernar Dias (1), Fernando Carreño (1), Victória Etges Helfer (1), Laura Bem Olivo (1), Keli Jaqueline Staudt (1), Fabíola Schons Meyer (2), Ana Paula Herrmann (2), Stela Maris Kuze Rates (1), Fabiano Barreto (3), Bibiana Verlindo de Araújo (1), Iñaki F. Trocóniz (4,5), Teresa Dalla Costa (1)
(1) Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. (2) Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. (3) Federal Laboratory of Animal and Plant Health and Inspection – LFDA/RS, Porto Alegre, Brazil (4) Pharmacometrics & Systems Pharmacology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. (5) IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
Introduction: Schizophrenia (SCZ) is a chronic mental disorder associated with a dysregulation in brain dopaminergic system[1]. Quetiapine (QTP) is an antipsychotic that modulates brain catecholamine concentrations, as dopamine (DA), playing a role in SCZ treatment[2], and presenting a high therapeutic variability. Nanoencapsulated QTP (QLNC) increased cortical unbound drug concentrations in schizophrenia phenotyped rats (SPR), restoring QTP concentrations to those observed in naïve animals[3].
Objectives: We aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to describe extracellular DA concentrations in naïve rats and SPR after administration of non-encapsulated QTP (FQ) and QLNC.
Methods: Protocol approved by CEUA/UFRGS (#31001). The effect of FQ and QLNC on medial prefrontal cortex extracellular DA concentration on naïve and SPR offspring was investigated using intracerebral microdialysis[2,4] in male and female naïve and SPR animals that received 5 mg/kg i.v. bolus dose of FQ or QNLC (n=5/7 animals/group). Data analysis was performed by populational approach using NONMEM (version 7.4, ICON). A semi-mechanistic population PK model previously described QTP unbound concentrations in plasma and brain following FQ and QLNC administration to naïve and SPR[4] was used to simulate QTP unbound brain concentrations after 5 mg/kg dosing, and incorporated in the PD model using linear interpolation. The covariates evaluated were sex, disease status reflected as prepulse inhibition (PPI) test[5], and formulation type. Model selection was guided by changes in the OFV, visual exploration of goodness of fit plots and precision of model parameters reflected as the RSE. Parameters were expressed as median and 95%CI of non-parametric bootstrap 1000 resampling.
Results: DA concentrations at baseline and over the course of the study were lower in SPR that received FQ. However, DA concentration on SPR that received QLNC were restored to concentrations observed in naïve animals. After QLNC dosing, a delay on DA peak was observed. Different structural models were investigated to fit DA concentrations after QTP dosing, starting with the description of naïve animals who received FQ. Indirect response and receptor biding models were tested. Based on the initial structure proposed for prolactin release[6], the final model describes the synthesis of DA in a pool compartment and its brain release and elimination [Rform: 0.311 ng/mL*h (CI: 0.225-0.428); Cpool,base: 1.16 ng/mL (CI: 0.82-1.47); DAbase: 0.288 ng/mL (CI: 0.274-0.304)]. DA release from pool compartment was dependent of QTP levels described as an effect compartment [Keo: 0.436 h-1 (CI: 0.371-0.661)]. The modulation of DA free concentrations in brain was included allowing DA concentrations return to baseline values [Kmod: 0.566 h-1 (CI: 0.352-0.967)]. The release rate of DA from pool compartment was influenced by the disease status, described by PPI, which was included as a linear covariate, and normalized by the mean of PPI groups. No significant differences were observed between sexes. To describe DA profiles in naïve rats and SPR who received QLNC, a nano effect was included, considering the blank nanoparticle effect on time of DA release from pool compartment [Dnano: 50401 ng/mL (CI: 6408-8193730); Kel,nano: 3.22 h-1 (CI: 2.54-4.32)].
Conclusion: The PK/PD model developed adequately described the reduced DA concentrations in SPR after FQ administration, and the return of DA levels following QLNC dosing to SPR, compared to naïve animals. The model also described the delayed DA peak after QLNC dosing. The differences observed on DA profiles between naïve and SPR animals after FQ and QNLC dosing cannot be attributed exclusively to changes in QTP pharmacokinetics associated to the disease or type of formulation administered. The need of a nano component to better describe QTP effect on DA concentrations may indicate that blank nanoparticles could alter the overall drug effect.
References:
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[2] McCutcheon RA et al. JAMA Psychiatry, 77: 201-210, 2019.
[3] Carreño F et al. JPET, 375: 49-58, 2020.
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[5] Carreño F et al. Schizophr Res, 218: 173-179, 2020.
[6] Movin-Osswald G and Hammarlund-Udenaes M. JPET, 274: 921-927, 1995.