加替沙星对老年慢性阻塞性肺病患者茶碱群体药代动力学的影响  

Effects of gatifloxacin on population pharmacokinetics of theophylline in elderly patients with chronic obstructive pulmonary disease

作　　者：仇向华[1] 梁红云[2] 王渊[1] 芮建中[1] 李金恒[1] 

机构地区：[1]南京大学医学院临床学院(南京军区南京总医院)药理科,江苏南京210002 [2]镇江市第二人民医院药剂科,江苏镇江212002

出　　处：《医学研究生学报》2008年第1期43-46,49,共5页Journal of Medical Postgraduates

基　　金：江苏省卫生厅科研项目奥赛康临床药学研究基金资助项目(批准号:P200502);镇江市科技计划项目资助(批准号:SH2006044);南京军区南京总医院科研基金资助项目(批准号:2005119)

摘　　要：目的:考察口服茶碱缓释片在老年慢性阻塞性肺病(COPD)患者中的群体药代动力学(PPK)特征,以及加替沙星对茶碱PPK的影响,为调整用药方案和个体化给药提供科学依据。方法:用非线性混合效应模型(NONMEM)程序,分析前瞻性收集先口服茶碱缓释片、再联用加替沙星的16例老年COPD患者256份茶碱血药浓度样本。一级吸收一房室开放模型能较好地拟合群体数据,估算吸收速率常数(ka)、清除率(CL/F)、分布容积(V)和滞后时间(ALAG)的个体间变异用指数模型,个体自身变异(残差误差)用加法模型。定量评价联合应用加替沙星(单用茶碱缓释片时设定加替沙星=0,联用茶碱缓释片和加替沙星时设定加替沙星=1)、体质量(BW)、年龄、生化指标等固定效应(协变量)对茶碱缓释片药代动力学(PK)参数的影响。结果:ka、CL/F、V和ALAG的群体标准值分别为1.38-1h、1.33 L/h、46.4 L和0.486 h,CL/F和V群体典型值的最终回归方程分别为C■/F=1.33×(1-0.138×加替沙星)和■=46.4×(BW/57)1.44。浓度实测值和个体预测值的平均绝对权重残差为(5.60±4.55)%。结论:合用加替沙星较单用茶碱缓释片时茶碱的CL/F下降13.8%,体质量对V的校正为体质量除以平均值的1.44次方,此特征对调整用药方案有一定的指导作用。Objective： To investigate the population pharmacokinetics （PPK） of the orally administered theophylline sustained-release tablets and the effect of gatifloxacin on theophylline PPK in the elderly patients with chronic obstructive pulmonary disease （COPD）, so as to obtain scientific support for the adjustment of the regimen schedule and individualized dosage. Methods： A Non-linear Mixed Effects Modeling （NONMEM） program was applied to the analysis of the population data of theophylline sustained-release tablets, based on the 256 steady-state serum concentrations of theophylline from 16 elderly COPD patients after oral administration of theophylline sustained-release tablets alone and then concurrently with gatifloxacin. The one-compartment open model with first-order absorption was employed as the basic pharmacokinetics model. Inter-individual variability of parameters ka, CL/F, V and ALAG were estimated with the exponential model, while intra-individual variability （residual error） with the addition model. Quantitative analyses were made of the effect of covariate, such as concurrent use of gatifloxacin （ GAT = 1, otherwise GAT = 0）, body weight （ BW）, age and biochemical indicators, on theophylline pharmacokinetic parameters. Results： The standard values of ka, CL/F, V and ALAG were 1.38 h^-1, 1.33 L/h, 46.4 L and 0.486 h, respectively. The final regression equations for typical population parameters CL/F and V were as follows： CL/F = 1.33 × （ 1 -0. 138 × GAT） ,V = 46.4 × （ BW/57 ）^1. 44. The mean absolute weighted residual of theophylline serum concentration between individual predicted and observed values was （ 5.60 ± 4. 55 ） %. Conclusion ： The clearance rate of theophylline sustained-release tablets decreases 13.8% when used concurrently with gatifloxacin. The best function adjustment for parameter V is the average to the power of 1.44 in proportion to body weight. These characteristics are useful for regulating the dose schedule.

关 键 词：茶碱 老年 慢性阻塞性肺病 群体药代动力学 非线性混合效应模型 加替沙星 

分 类 号：R969.1[医药卫生—药理学]