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Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

ABSTRACT: Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration-effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharmacodynamic (PD) model to correlate the drug kinetics to changes in dopamine (DA) medial prefrontal cortex extracellular concentrations determined by intracerebral microdialysis. Different structural models were investigated to fit DA concentrations after QTP dosing, and the final model describes the synthesis, release, and elimination of DA using a pool compartment. The results show that nanoparticles increase QTP brain concentrations and DA peak after drug dosing to SPR. To the best of our knowledge, this is the first study that combines microdialysis and PK/PD modeling in a neurodevelopmental model of SCZ to investigate how a nanocarrier can modulate drug PK and PD, contributing to the development of new treatment strategies for SCZ.

SUBMITTER: Dias BB

PROVIDER: S-EPMC11015084 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

Dias Bruna Bernar BB Carreño Fernando F Helfer Victória Etges VE Olivo Laura Ben LB Staudt Keli Jaqueline KJ Paese Karina K Barreto Fabiano F Meyer Fabíola Schons FS Herrmann Ana Paula AP Guterres Sílvia Stanisçuaski SS Rates Stela Maris Kuze SMK de Araújo Bibiana Verlindo BV Trocóniz Iñaki F IF Dalla Costa Teresa T

CPT: pharmacometrics & systems pharmacology 20240128 4

Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration-effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharma ...[more]

PMID: 38282365

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Project description:IntroductionSchizophrenia is a chronic mental disorder that worsens with each relapse. Long-acting injectable (LAI) antipsychotics may prevent the exacerbation of symptoms and occurrence of relapses through improved continuity of care. Different dose regimens are available for the LAIs aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), but their cost effectiveness is unclear.ObjectivesThe study aim was to compare costs and effects (relapses) of the different aripiprazole LAI dose regimens to inform clinical and US payer decisions.MethodsA state-transition model calculated the outcomes of eight LAI dose regimens based on their relapse rates. As effectiveness data from randomized controlled trials were unavailable, relapse rates were modeled using pharmacokinetic and pharmacodynamic evidence. These described blood plasma levels of aripiprazole as a function of AM and AL dose regimens and described the probability of relapse as a function of aripiprazole blood plasma levels. The analysis had a time horizon of 1 year and took the US healthcare payer perspective. The incremental cost per relapse avoided and the probability of cost effectiveness were calculated in deterministic and probabilistic analyses. Scenario analyses explored the model's main assumptions, and results were validated against external data and other cost-effectiveness analyses.ResultsMonthly administration of AM 400 mg consistently yielded the lowest predicted number of relapses across deterministic, probabilistic, and scenario analyses. The costs of treatment and relapses were projected to be the lowest with a monthly administration of AL 441 mg. The incremental cost per relapse avoided with AM 400 mg ranged from AM 400 mg being dominant to $US83,300. From willingness-to-pay thresholds of $US30,000 per relapse avoided, the probability of cost effectiveness was highest for AM 400 mg. The validation showed alignment with external data.ConclusionThe analysis highlighted the robustness of the novel framework based on pharmacokinetic and pharmacodynamic evidence and demonstrated an application in a postmarketing setting.

Project description:Salmonella typhimurium is a highly transmissible pathogen in rabbits that causes significant losses. Danofloxacin shows excellent efficacy against S. typhimurium infections. However, there are few reports of the pharmacokinetic/pharmacodynamic (PK/PD) modeling of danofloxacin against this pathogen. The aim of this study was to evaluate the in vivo PK/PD relationship of danofloxacin in rabbits infected with S. typhimurium. We used the reduction of bacterial burden in the blood, liver, spleen, and lung as the target PD endpoints, and determined the PK/PD indexes that best correlated with the efficacy and its corresponding magnitude. Danofloxacin was administrated orally to experimentally S. typhimurium-infected rabbits once daily for three successive days. The concentrations of danofloxacin in the serum and the bacterial burden in the blood, liver, spleen, and lung were determined. The PK/PD relationships of danofloxacin against S. typhimurium were evaluated using a Sigmoid Emax model. The results showed that the area under the concentration-time curve from 0 to 24 h/minimum inhibitory concentration (AUC24 h/MIC) ratio correlated well with the in vivo antibacterial effectiveness in different organs, with an r2 of 0.8971, 0.9186, 0.9581, and 0.8708 in the blood, liver, spleen, and lung, respectively. The AUC24 h/MIC ratios for the bactericidal effect (3 × Log10 colony forming units/mL reductions) were 121.30, 354.28, 216.64, and 228.66 in the blood, liver, spleen, and lung, respectively, indicating that the in vivo effectiveness of danofloxacin against S. typhimurium using bacterial reduction in different organs as PD endpoints was not identical. This study illustrated that the selection of the target organ for bacterial reduction determination had little effect on best PK/PD parameter determination, but is critical for parameter magnitude calculation in antimicrobial PK/PD modeling, and furthermore, has an impact on the rational dosage optimization process.

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Dataset Information

Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

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Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

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