阿片类物质成瘾者服用美沙酮口服液的群体药动学研究

Population pharmacokinetics of methadone oral solution in opioid addicts

目的应用非线性混合效应模型法考察阿片类物质成瘾者服用美沙酮口服液的群体药动学特征。方法回顾性收集美沙酮维持治疗患者150例896个血药浓度监测数据。以患者年龄、性别、体重、美沙酮日剂量、肝肾功能及合并抗病毒药物等为协变量,采用具有一级吸收和消除的一室模型拟合数据,并通过自举法(Bootstrap)对模型进行验证。结果单独服用美沙酮的表观清除率(CL/F)为10.22 L·h^(-1),合并用药为22.3 L·h^(-1);单独用药的消除速率常数(Ke)为0.02 h^(-1),合并用药为0.05 h^(-1);单独用药的半衰期(T1/2)为30.21 h,合并用药为13.86 h;单独用药和合并用药表观分布容积(V/F)和吸收速率常数(Ka)均分别为446 L和0.904 h^(-1)。最终模型Bootstrap法的数据拟合成功率达99.7%,模型评价结果显示该模型及参数估算值可靠稳定。结论群体药动学结果显示,合并用药对阿片类物质成瘾者服用美沙酮口服液药动学参数CL有显著影响,对Ka和V/F无影响。

OBJECTIVE To investigate the population pharmacokinetic characteristics of methadone oral solution in opioid addicts by using nonlinear mixed effects model approach(NONMEM).METHODS Totally 896 plasma concentrations were retrospectively collected from 150 patients(113males and 37 females)under methadone maintenance treatment.Using age,sex,body mass,daily dose of methadone,liver and kidney function and co-therapy with antivirals as covariates,a one-compartment model with first-order absorption and elimination was used to analyze the data,and was assessed using Bootstrap.RESULTS The apparent clearance rate(CL/F)was 10.22 L·h^(-1)for methadone alone and22.3 L·h^(-1)for combinations.The elimination rate constant(Ke)was 0.02 h^(-1)for methadone alone and0.05 h^(-1)for combinations.The half-life of combinations was 13.86 h,and that of monotherapy was 30.21 h.The apparent volume of distribution(V/F)and absorption rate constant(Ka)were 446 L and 0.904 h^(-1)separately for both groups.The data fitting success rate of the final model by Bootstrap method reached99.7%,and model evaluation showed that the model and the estimated parameters were reliable and stable.CONCLUSION CL is significantly affected by combined drug use,but Kaand V are not.