茶碱在老年慢性阻塞性肺疾病患者中的群体药动学

目的：建立茶碱在老年慢性阻塞性肺疾病患者中的群体药动学（PPK）模型，并获取药动学参数，为临床制定个体化给药方案提供参考。方法：收集2014年4—12月某院诊断为慢性阻塞性肺疾病应用茶碱治疗的68例老年患者的血药浓度监测数据及临床资料，运用非线性混合效应模型法（NONMEN）定量分析性别、年龄、体质量及肝肾功能等因素对药动学参数的影响，最终建立PPK模型。采用拟合优度、自举法和可视化检验对最终模型的性能进行内部验证。结果：茶碱的药动学符合一室模型，最终模型公式为：CL=θ_CL×（WT/63）^θWT×exp（η_CL），V=θ_V×exp（η_V），其中的协变量为体质量，模型CL和V的群体典型值分别为0.849 L·h^-1，13.7 L。拟合优度、自举法和可视化检验的评价结果表明最终模型稳定，预测结果可靠。结论：建立的PPK模型能较好地描述茶碱在老年慢性阻塞性肺疾病患者中的药动学特点，患者体质量对参数CL有显著性影响。

Population pharmacokinetics of theophylline in elderly patients with chronic obstructive pulmonary disease

OBJECTIVE To establish the population pharmacokinetics (PPK) model of theophylline in elderly patients with chronic obstructive pulmonary disease, and to obtain the individual pharmacokinetic parameters for designing clinical individualized regimen.METHODS Sixty eight elderly patients in our hospital diagnosed as chronic obstructive pulmonary disease were included from April 2014 to November 2014. TDM data of theophylline and clinical materials were collected. The influences of covariate effects, including gender, age, body weight, liver and kidney functions, on parameters of PPK were estimated by nonlinear mixed effect model (NONMEM) method, and a population pharmacokinetics model was constructed. The performance of final model was internally assessed by goodness-of-fit, bootstrapping and visual predictive checking.RESULTS The pharmacokinetic profile of theophylline fitted best to one-compartmental model. The final model formula was as follows:CL=θ_CL×(WT/63)^θ_WT× exp(η_CL), V=θ_V× exp(η_V). The body weight was identified as the most significant covariate in the final model. Typical values of clearance and volume of distribution in the final model were 0.849 L·h^-1 and 13.7 L, respectively. The stability and predictive performance were accepted by goodness-of-fit, bootstrapping and visual predictive checking.CONCLUSION With application of NONMEN, a population pharmacokinetics model of theophylline is established, which is capable of depicting pharmacokinetics of theophylline in elderly patients with chronic obstructive pulmonary disease. It is found that body weight can affect theophylline clearance.