瑞舒伐他汀钙治疗中国高脂血症人群的药效动力学探索

中国临床药理学与治疗学 ›› 2010, Vol. 15 ›› Issue (8): 894-900.

瑞舒伐他汀钙治疗中国高脂血症人群的药效动力学探索

杨娟, 李禄金, 何迎春, 许羚, 吕映华, 张密, 刘红霞, 郑青山

上海中医药大学药物临床研究中心,上海201203

收稿日期:2010-05-23 修回日期:2010-06-12 出版日期:2010-08-26 发布日期:2020-09-17
通讯作者: 郑青山,男,教授,博士生导师,主要从事定量药理学和生物统计学研究。Tel: 021-51323006 E-mail:zhengqscn@21cn.com
作者简介:杨娟,女,硕士,助理研究员,研究方向:定量药理学和生物统计学。Tel: 021-51322420 E-mail: janeyang5006@163.com
基金资助:
上海市教委重点学科建设项目 (J50303);上海市高校E研究院项目(E0308)和2007年上海高校选拔培养优秀青年教师科研专项基金资助(SZY07027)

An exploring study on the pharmacodynamics of rosuvastatin in Chinese hypercholesterolemic patients

YANG Juan, LI Lu-jin, HE Ying-chun, XU Ling, LV Ying-hua, ZHANG Mi, LIU Hong-xia, ZHENG Qing-shan

Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai 201203, China

Received:2010-05-23 Revised:2010-06-12 Online:2010-08-26 Published:2020-09-17

摘要/Abstract

摘要： 目的: 建立舒伐他汀钙治疗中国高脂血症人群的群体药效学模型,考察单位体重用药剂量和低密度脂蛋白胆固醇(LDL-C)的量效关系。方法: 从已有的临床研究中,选择合适的受试者,提取其主要疗效指标(服用瑞舒伐他汀钙8周后LDL-C下降率),及潜在的可能对LDL-C下降率有影响的指标(包括受试者所属试验、年龄、性别、体重和LDL-C基线值等)。用NONMEM软件进行模型拟合和群体药效学参数的估算。用Bootstrap法和蒙特卡洛模拟法分别对最终群体药效学模型进行验证和预测。结果: Sigmoidal E_max药效学模型较好地拟合了瑞舒伐他汀钙治疗中国高脂血症人群的量效关系,所属试验、年龄、性别、体重和LDL-C基线值等因素对其无影响,最终模型的药效学参数E_max、ED₅₀和γ分别为53.9%,0.072 mg/kg和3.76,且参数的相对标准误均较小。Bootstrap法证明了最终模型具有较好的稳定性,蒙特卡洛模拟预测药效的95%可信区间包含了约50%受试者的实测药效。结论: 本研究用群体分析方法建立了中国高脂血症人群应用瑞舒伐他汀钙的药效学模型,反映了约50%受试者用药后的药效学特征,说明除剂量外,影响药效因素众多,有待进一步探索。

关键词: 瑞舒伐他汀钙, LDL-C下降率, 群体药效学, NONMEM

Abstract: AIM: To develop a population pharmacodynamic (PPD) model for investigating the relationship between dose per kilogram body weight of rosuvastatin and LDL-C reduction in Chinese hypercholesterolemic patients.METHODS: Eligible patients were selected from relevant clinical trials and end point data were extracted for each patient. The primary efficacy end point was the mean percentage of change in LDL-C at 8 weeks from baseline. Potential covariates including trial, age, gender, body weight and baseline LDL-C levels were collected. Population modeling was performed with NONMEM. Bootstrap and Monte Carlo simulation was performed to assess the model robustness and prediction, respectively.RESULTS: Sigmoidal Emax model successfully described the dose-response relationship of rosuvastatin in Chinese hyperlipoidemic patients. The covariates did not significantly influence any hypercholesterolemic parameters. The population parameter estimates of E_max, ED₅₀ and gamma were 53.9%, 0.072 mg/kg and 3.76, and their relative standard errors were all small. Model robustness was validated by a nonparametric bootstrap. The 95% confidence interval of Monte Carlo simulation included about 50% patients' observed values of LDL-C reduction.CONCLUSION: This study developed a pharmacodynamic model for rosuvastatin in Chinese hypercholesterolemic patients with population method which described the pharmacodynamic characteristic of about 50% patients. The result indicates LDL-C reduction of rosuvastatin may be impacted by numerous factors except for dose, which should be investigated further.

Key words: Rosuvastatin, LDL-C reduction, Population pharmacodynamics, NONMEM

中图分类号:

R311

杨娟, 李禄金, 何迎春, 许羚, 吕映华, 张密, 刘红霞, 郑青山. 瑞舒伐他汀钙治疗中国高脂血症人群的药效动力学探索[J]. 中国临床药理学与治疗学, 2010, 15(8): 894-900.

YANG Juan, LI Lu-jin, HE Ying-chun, XU Ling, LV Ying-hua, ZHANG Mi, LIU Hong-xia, ZHENG Qing-shan. An exploring study on the pharmacodynamics of rosuvastatin in Chinese hypercholesterolemic patients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(8): 894-900.

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