Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat

Wong, Yin Cheong; Ilkova, Trayana; Wijk, Rob C. van; Hartman, Robin; Lange, Elizabeth C. M. de

doi:10.1016/j.ejps.2017.10.031

Cited by 10 publications

(10 citation statements)

References 64 publications

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“…Clonidine: Devoto et al, 2001 ; Gobbi et al, 2001 . Raclopride: Wong et al, 2018 ; Devoto et al, 2019 ). Drugs were dissolved in sterile distilled water, and IP or subcutaneously (SC) administered in a volume of 1 ml/kg body weight.…”

Section: Methodsmentioning

confidence: 99%

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex

et al. 2020

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Section: Methodsmentioning

confidence: 99%

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex

et al. 2020

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“…PK and RO data from subjects administered with the metabolite (paliperidone or norclozapine) alone were also collected. The main exclusion criteria were (1) formulations other than the conventional intravenous (IV) and subcutaneous dosage forms for rats and conventional IV and oral dosage forms for humans; (2) data from anesthetized rats, since anesthesia can cause dramatic changes in the PK and RO time profile; (3) data from special patient populations (eg, pediatrics and elderly); (4) publications that were not fully accessible; (5) studies that did not report drug formulation, administration route, or dose; and (6) studies providing RO data without specifying the time at which the measurements were performed with respect to the drug administration. The details of each included study are summarized in .…”

Section: Methodsmentioning

confidence: 99%

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Wong

Centanni

Lange

2019

The Journal of Clinical Pharma

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Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK‐Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood‐brain barrier parameters including the expression and efflux transport kinetics of P‐glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model. Based on the simulated drug and metabolite concentrations in brainECF, drug‐D2 receptor binding kinetics (association and dissociation rates) were incorporated in MoBi to predict RO. From an extensive literature search, 32 plasma PK data sets (16 from rat and 16 from human studies) and 23 striatum RO data sets (13 from rat and 10 from human studies) were prepared and compared with the model predictions. The rat PBPK‐RO model adequately predicted the plasma concentrations of the parent drugs and metabolites and the RO levels. The human PBPK‐RO model also captured the plasma PK and RO levels despite the large interindividual and interstudy variability, although it tended to underestimate the plasma concentrations and RO measured at late time points after risperidone dosing. The developed human PBPK‐RO model was successfully applied to predict the plasma PK and RO changes observed after risperidone dose reduction in a clinical trial in schizophrenic patients.

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“…target binding and activation, and downstream physiological responses) is equally important for understanding drug effects [11,12]. Among others, receptor occupancy [23,25], EEG measures [28,42], hormone release [30] have been used to characterize the pharmacodynamic response of CNS drugs. The mathematical linkage of PD responses to the drug exposure has been extensively reviewed by Danhof et al [43].…”

Section: Pd Modelsmentioning

confidence: 99%

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

Brink

Hankemeier

Graaf

et al. 2018

Expert Opinion on Drug Discovery

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Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.

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Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat

Cited by 10 publications

References 64 publications

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

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