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. 2024 Jan 23;17(2):148.
doi: 10.3390/ph17020148.

Population Pharmacodynamic Models of Risperidone on PANSS Total Scores and Prolactin Levels in Schizophrenia

Zhiwei Huang  1 , Lei Zhang  1 , Yan Li  1 , Yimin Yu  1 , Yifeng Shen  1 , Xiujia Sun  1 , Kun Lou  2 , Hongmei Luo  2 , Zhibin Meng  2 , Huafang Li  1   3   4 , Yumei Wei  1
Affiliations

Population Pharmacodynamic Models of Risperidone on PANSS Total Scores and Prolactin Levels in Schizophrenia

Zhiwei Huang et al. Pharmaceuticals (Basel). .

Abstract

Currently, research predominantly focuses on evaluating clinical effects at specific time points while neglecting underlying patterns within the treatment process. This study aims to analyze the dynamic alterations in PANSS total scores and prolactin levels in patients with schizophrenia treated with risperidone, along with the influencing covariates. Using data from an 8-week randomized, double-blind, multicenter clinical trial, a population pharmacodynamic model was established for the PANSS total scores of and prolactin levels in patients treated with risperidone. The base model employed was the Emax model. Covariate selection was conducted using a stepwise forward inclusion and backward elimination approach. A total of 144 patients were included in this analysis, with 807 PANSS total scores and 531 prolactin concentration values. The PANSS total scores of the patients treated with risperidone decreased over time, fitting a proportionally parameterized sigmoid Emax model with covariates including baseline score, course of the disease, gender, plasma calcium ions, and lactate dehydrogenase levels. The increase in prolactin levels conformed to the ordinary Emax model, with covariates encompassing course of the disease, gender, weight, red blood cell count, and triglyceride levels. The impacts of the baseline scores and the course of the disease on the reduction of the PANSS scores, as well as the influence of gender on the elevation of prolactin levels, each exceeded 20%. This study provides valuable quantitative data regarding PANSS total scores and prolactin levels among patients undergoing risperidone treatment across various physiological conditions.

Keywords: PANSS total scores; population pharmacodynamics; prolactin; risperidone; schizophrenia.

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Conflict of interest statement

Kun Lou, Hongmei Luo, and Zhibin Meng are employees of CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. All authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart of the enrolled patients.
Figure 2
Figure 2
Covariate effect evaluation of the population pharmacodynamic model of PANSS total scores. (A) Effects on pharmacodynamic parameters are expressed relative to a reference patient (male, with baseline plasma calcium = 2.3 µmol/L, course of the disease = 5 years, and lactate dehydrogenase = 155 U/L). (B) Effects on PANSS total score changes at week 8 are expressed relative to the reference patient. (C) Simulated PANSS total score changes of a typical patient over treatment time. Data are estimates (95% CI). Dotted lines represent the reference ±20%. CI: confidence interval; E0: baseline; Emax: maximum effect; ET50: time to 50% Emax; PANSS: Positive and Negative Syndrome Scale; γ: Hill coefficient.
Figure 3
Figure 3
Covariate effect evaluation of the population pharmacodynamic model of prolactin levels. (A) Effects on pharmacodynamic parameters are expressed relative to a reference patient (male, with baseline course of the disease = 5 years, red blood cells = 4.5 × 1012/L, triglycerides = 0.9 mmol/L, and weight = 60 kg). (B) Effects on prolactin levels change at week 2 are expressed relative to the reference patient. (C) Simulated prolactin level changes of a typical patient over treatment time. Data are estimates (95% CI). Dotted lines represent the reference ±20%. CI: confidence interval; E0: baseline; Emax: maximum effect.
Figure 4
Figure 4
Visual predictive check for the final population pharmacodynamic model of PANSS total scores. Blue circles are the observations. Red solid lines represent the observed median; blue solid lines represent the observed 2.5th and 97.5th percentiles. Shaded bands are simulation-based 95% prediction intervals for the median, 2.5th, and 97.5th percentiles. PANSS: Positive and Negative Syndrome Scale.
Figure 5
Figure 5
Visual predictive check for the final population pharmacodynamic model of prolactin levels. Blue circles are the observations. Red solid lines represent the observed median; blue solid lines represent the observed 2.5th and 97.5th percentiles. Shaded bands are simulation-based 95% prediction intervals for the median, 2.5th, and 97.5th percentiles.
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