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Population pharmacokinetic-pharmacodynamic (PopPK/PD) modeling of risperidone and its active metabolite in Chinese schizophrenia patients
Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China.;Peking Univ, Sch Pharmaceut Sci, Beijing 100191, Peoples R China..
Guangzhou Med Univ, Guangzhou Brain Hosp, Dept Pharm, Guangzhou, Guangdong, Peoples R China..
Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China.;Peking Univ, Sch Pharmaceut Sci, Beijing 100191, Peoples R China..
Capital Med Univ, Ctr Schizophrenia, Beijing Inst Brain Disorders, Lab Brain Disorders, Beijing 100088, Peoples R China.;Capital Med Univ, Beijing Anding Hosp, Dept Psychiat, Beijing Key Lab Mental Disorders, Beijing 100088, Peoples R China..
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2016 (English)In: International journal of clinical pharmacology and therapeutics, ISSN 0946-1965, Vol. 54, no 5, 378-389 p.Article in journal (Refereed) PublishedText
Abstract [en]

Purpose: Risperidone is a second-generation antipsychotic agent commonly used in the treatment of 31.1% of schizophrenia patients in China, it is the most commonly-prescribed antipsychotic agent. Despite the abundant use of risperidone, population pharmacokinetic-pharmacodynamic models of risperidone have not been performed in Chinese schizophrenia patients. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PopPK/PD) model to describe the PK behavior and efficacy of risperidone and 9-hydroxy-risperidone (active metabolite) in Chinese patients. Methods: Plasma concentration data (702 measurements from 131 patients) and positive and negative syndrome scale (PANSS) scores (258 observations from 56 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCEI). The influence of potential covariates was evaluated. Model robustness was assessed using external validation, nounalized prediction distribution error, nonparametric bootstrap, and visual predictive check approaches. Results: Risperidone concentration data were well described by a one-compartmental model incorporating an additional compartment that refers to the concentration profiles of 9-hydroxy-risperidone. A complex absorption procedure was incorporated into the model to describe the metabolism of risperidone to 9-hydroxy-risperidone in the gastrointestinal (GI) tract. A binomial distribution in the estimated clearance (CL) of risperidone has been identified in our model. Decrease in PANSS score along with total AUC (AUC(total)) of risperidone and 9-hydroxy-risperidone was best characterized by an E-max model with 3 transit compartments describing the delay of drug effect. Conclusions: Considerable differences in PK behavior and drug effect of risperidone have been identified among Chinese extensive metabolizing (EM) and poor metabolizing (PM) patients. This PopPK/PD model may fulfill individualized treatment in clinical practice and may potentially be transferred to other antipsychotic therapies.

Place, publisher, year, edition, pages
2016. Vol. 54, no 5, 378-389 p.
Keyword [en]
risperidone, Chinese, active metabolite, PopPK/PD, schizophrenia
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-298687DOI: 10.5414/CP202498ISI: 000376334300008PubMedID: 27007997OAI: oai:DiVA.org:uu-298687DiVA: diva2:947165
Available from: 2016-07-07 Created: 2016-07-06 Last updated: 2016-07-07Bibliographically approved

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