Abstract

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, normalized 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.

Author Details

Authors

• Shuangmin Ji^{1, 4}
• Dewei Shang⁵
• Kehua Wu^{1, 4}
• Anning Li^{2, 3}
• Xiwei Li⁷
• Chenhui Deng⁶
• Liang Li^{1, 4}
• Tianyan Zhou^{1, 4}
• Chuanyue Wang^{2, 3}*
• Wei Lu^{1, 2, 4}*

Departments

• ¹ State Key Laboratory of Natural and Biomimetic Drugs, Peking University,
• ² Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University),
• ³ Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University,
• ⁴ School of Pharmaceutical Sciences, Peking University, Beijing,
• ⁵ Department of Pharmacy, Guangzhou Brain Hospital, Guangzhou Medical University, Guangzhou, China,
• ⁶ Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, and
• ⁷ Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China

Address

Wei Lu, PhD
State Key Laboratory of Natural and Biomimetic Drugs
Peking University, Beijing, 100191, China
or
Chuanyue Wang, MD
Center of Schizophrenia
Beijing Institute for Brain Disorders
Laboratory of Brain Disorders (Capital Medical University)
Ministry of Science and Technology, Beijing 100088, China
Email: [email protected] or [email protected]

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