单剂量长效利培酮注射液在中国精神分裂症患者体内的药代动力学、药效学和安全性研究

doi:10.5246/jcps.2021.03.016

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (3): 206-217.DOI: 10.5246/jcps.2021.03.016

单剂量长效利培酮注射液在中国精神分裂症患者体内的药代动力学、药效学和安全性研究

李晓娇¹^,^#, 栾树鑫²^,^#, 张洪¹, 万洪泉², 陈红¹, 刘成娇¹, 刘畅², 丁艳华¹^,^*()

1. 吉林大学第一医院 I期药物临床试验研究室, 吉林长春 130021
2. 吉林大学第一医院心理卫生科, 吉林长春 130021

收稿日期:2020-09-18 修回日期:2020-10-29 接受日期:2020-11-13 出版日期:2021-03-29 发布日期:2021-03-29
通讯作者: 丁艳华
作者简介:
+ Tel.: +86-431-88782168, E-mail: dingyanhua2003@126.com
基金资助:
The National Major Scientific and Technological Special Project for "Significant New Drug Development" during the Twelfth Five-year Planning Period of China (Grant No. 2014ZX09303303).

Pharmacokinetics, pharmacodynamics and safety of a single-dose long-acting Risperidone injection in Chinese patients with schizophrenia

Xiaojiao Li¹^,^#, Shuxin Luan²^,^#, Hong Zhang¹, Hongquan Wan², Hong Chen¹, Chengjiao Liu¹, Chang Liu², Yanhua Ding¹^,^*()

1 Phase I Clinical Trial Unit, First Hospital, Jilin University, Jilin 130021, China
2 Department of Mental Health, First Hospital, Jilin University, Jilin 130021, China

Received:2020-09-18 Revised:2020-10-29 Accepted:2020-11-13 Online:2021-03-29 Published:2021-03-29
Contact: Yanhua Ding
About author:
# These authors contributed equally to this work.

摘要/Abstract

摘要：

本研究旨在探讨在中国精神分裂症患者中应用单剂量长效利培酮注射液后的药代动力学、药效学、不良事件及其相互关系。精神分裂症患者(6名女性和7名男性)被纳入这项研究。给药后连续采血至63天, 应用液质联用方法分析血浆药物浓度。通过监测不良事件、临床实验室结果变化、12导联心电图、生命体征、体格检查和注射部位反应来评价安全性和耐受性。采用锥体外系症状评定量表(ESRS)对锥体外系症状进行评估, 采用阳性与阴性症状量表(PANSS)和简明精神病量表(BPRS)评价疗效。13名入组受试者中12人完成了本试验。除催乳素水平和体重外, 平均临床实验室检验值、生命体征和心电图参数几乎未发生有临床意义的变化。无严重不良事件发生, 所观察到的不良事件均是可逆的。观察到PANSS和PANSS衍生的BPRS总分均有显著改善。药代动力学参数的均值(标准差, 变异系数)为: C_max, 8.954 (8.059, 90.0%) ng/mL; AUC_0–t, 2453 (1156, 47.1%) ng?h/mL; AUC_0–∞, 2472 (1160, 46.9%) ng?h/mL; t_max, 830.0 (min: 744.0, max: 984.0, 11.8%) h; t_1/2, 68.56 (10.77, 15.7%) h。长效利培酮的药代动力学特征在个体间存在较高的变异, 而本研究中精神分裂症患者药代动力学、疗效、不良事件之间无明显相关性。

关键词: 长效利培酮注射液, 单剂量, 药代动力学, 液相色谱-质谱联用, 中国精神分裂症患者

Abstract:

In the present study, we aimed to determine the pharmacokinetics (PK), pharmacodynamics (PD), adverse events (AEs), and their relationships in Chinese patients with schizophrenia after a single dose of long-acting risperidone. Schizophrenic patients (six females and seven males) were enrolled in this study. Serial blood samples were collected after drug administration during 63 d, and the drug concentrations were analyzed by LC-MS/MS. Safety and tolerance were evaluated by monitoring the AEs, changes in clinical laboratory results, 12-lead ECG, vital signs, physical examination, and injection-site reactions. The extrapyramidal symptoms were evaluated using the ESRS. Efficacy was evaluated by the PANSS and BPRS. Twelve out of the 13 participants completed the trial. There were few clinically meaningful changes in mean clinical laboratory values, vital signs, or ECG parameters, except for the prolactin level and body weight. There were no serious AEs, and those observed were reversible. Significant clinical improvements in PANSS and PANSS-derived BPRS total scores were observed. The mean (standard deviation, coefficient of variation) values for these PK parameters were as follows: C_max, 8.954 (8.059, 90.0%) ng/mL; area under the curve AUC_0–t, 2453 (1156, 47.1%) ng?h/mL; AUC_0–∞, 2472 (1160, 46.9%) ng?h/mL; t_max, 830.0 (min: 744.0, max: 984.0, 11.8%) h; and t_1/2, 68.56 (10.77, 15.7%) h. The PK characteristics of long-acting risperidone showed a high level of inter-individual variation, while there were no clear correlations between PK, efficacy and AEs among the patients in the present study.

Key words: Long-acting risperidone injection, Single-dose, Pharmacokinetics, LC-MS/MS, Chinese schizophrenic patients

Supporting:

李晓娇, 栾树鑫, 张洪, 万洪泉, 陈红, 刘成娇, 刘畅, 丁艳华. 单剂量长效利培酮注射液在中国精神分裂症患者体内的药代动力学、药效学和安全性研究[J]. 中国药学(英文版), 2021, 30(3): 206-217.

Xiaojiao Li, Shuxin Luan, Hong Zhang, Hongquan Wan, Hong Chen, Chengjiao Liu, Chang Liu, Yanhua Ding. Pharmacokinetics, pharmacodynamics and safety of a single-dose long-acting Risperidone injection in Chinese patients with schizophrenia[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(3): 206-217.

图/表 10

Table 1. Demographic data and baseline characteristics of patients (six females and seven males).

Figure 1. Mean and individual plasma levels of risperidone after a single dose (25 mg) of long-acting risperidone in 12 patients with schizophrenia (C-T profiles (A) and Log C-T profiles (B)).

Table 2. PK parameters of risperidone long-acting injection (25 mg), in comparison with published data[9].

Table 3. Total PANSS scores at various time points (baseline, day 30 and day 63).

Table 4. Changes in PANSS and BPRS scores from baseline to day 63 (n = 11).

Figure 2. The profiles of PANSS scores at baseline and on day 30 and day 63. (A) The PANSS scores were not obtained for subject 005. (B) Mean changes in PANSS scores and PANSS-derived BPRS scores from baseline to day 63. (C) Mean changes in prolactin levels from baseline to day 63. (D) Mean changes in the weight of subjects from baseline to day 63.

Table 5. Changes in prolactin and weight from baseline to day 63 (n = 12).

Table 6. Incidence of AEs (n = 13).

Figure 3. Mean systolic pressure, diastolic pressure, and heart rate in the supine (A) and standing position of 12 patients with schizophrenia after a single dose (25 mg) of long-acting risperidone (B).

Figure 4. The profiles of PK parameters (Cmax and AUC0–t), PANSS changes, and the total number of AEs. (The PANSS scores were not obtained for subject 005).

参考文献 22

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单剂量长效利培酮注射液在中国精神分裂症患者体内的药代动力学、药效学和安全性研究

Pharmacokinetics, pharmacodynamics and safety of a single-dose long-acting Risperidone injection in Chinese patients with schizophrenia

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