氟西汀总活性成分在抑郁患者中的群体药动学研究  

Population pharmacokinetics for total active moiety of fluoxetine in patients with depression

作　　者：钟彩妮 曾环思[2] 钟易霖 李维柯 刘运宇 王裕锋 刘云[2] 吴伟翔 古嘉瑜 ZHONG Caini;ZENG Huansi;ZHONG Yilin;LI Weike;LIU Yunyu;WANG Yufeng;LIU Yun;WU Weixiang;GU Jiayu(Shantou University Medical College,Shantou 515041,China;Shenzhen Mental Health Center&Shenzhen Kangning Hospital,Shenzhen 518020,China;Shenzhen People’s Hospital,Shenzhen 518020,China)

机构地区：[1]汕头大学医学院,广东汕头515041 [2]深圳市精神卫生中心/深圳市康宁医院,广东深圳518020 [3]深圳市人民医院,广东深圳518020

出　　处：《广东药科大学学报》2024年第4期100-107,共8页Journal of Guangdong Pharmaceutical University

基　　金：广东省高水平临床重点专科(深圳市配套建设经费)资助项目(SZGSP013);广东省自然科学基金项目(2023A1515011936);深圳市康宁医院院内课题项目(KN2023B017)。

摘　　要：目的建立抑郁患者氟西汀(fluoxetine,FLX)总活性成分(total active moiety,TAM)的群体药动学(PPK)模型并研究其影响因素,为个体化用药提供参考。方法回顾性收集2020年1月-2023年12月深圳市康宁医院154例服用FLX治疗住院患者的用药情况、FLX和去甲氟西汀(norfluoxetine,NFLX)血药浓度、肝肾功能水平、血脂水平及细胞色素P4502D6酶(CYP2D6)基因型等临床资料,计算FLX和NFLX浓度之和为血浆TAM浓度,采用非线性混合效应模型法(NONMEM)建立TAM浓度PPK模型,采用拟合优度图(GOF)、正态化预测分布误差法(NPDE)和自举法(Bootstrap)对模型的稳定性和预测性能进行评估。基于最终模型的显著协变量,模拟不同人群不同剂量TAM浓度的变化情况,拟合达稳态时间并推荐给药剂量。结果154例住院患者570个血药浓度数据包括FLX(n=285)和NFLX(n=285),建立了TAM的一阶吸收和消除的一房室模型,体重(WT)是影响表观清除率(CL/F)的显著协变量,最终模型参数CL/F、表观分布容积(V/F)和吸收速率常数(Ka)的群体典型值分别为2.91 L/h、734 L和0.3 h^(-1),模型表示为:CL/F(L·h^(-1))=2.91×(WT/55)0.531,V/F(L)=734,Ka(h^(-1))=0.3(固定值)。蒙特卡洛模拟结果显示,TAM浓度达稳态时间为6~11周,给药剂量相同,体重越轻达稳时间越长,体重小于70 kg的患者,最佳给药方案为10~30 mg,大于70 kg为20~40 mg。结论成功建立了服用FLX治疗的抑郁患者TAM浓度的PPK模型,最终模型稳定可靠,低体重人群应选择较低剂量的FLX,避免药物蓄积产生不良反应。Objective To establish a population pharmacokinetic(PPK)model for total active moiety(TAM)of fluoxetine(FLX)in patients with depression and to study its influencing factors,providing a reference for individualized medication.Methods The clinical data of inpatients treated with FLX in Shenzhen Kangning Hospital from January 2020 to December 2023 were collected retrospectively,including medication,plasma concentrations of FLX and norfluoxetine(NFLX),liver and kidney function levels,blood lipid levels,and cytochrome enzyme P4502D6(CYP2D6)genotypes.The sum of FLX and NFLX concentrations was calculated as plasma TAM concentrations.The PPK model was established by using the nonlinear mixed-effect modeling(NONMEM).The stability and prediction performance of the model were evaluated by using goodness-of-fit map(GOF),normalized prediction distribution error method(NPDE),and Bootstrap method(Bootstrap).Based on the significant covariates of the final model,the changes of concentrations across different populations and different doses were simulated,and the steady-state time was fitted and the dose was recommended.Results A one-compartment model with first-order absorption and elimination was established by FLX and NFLX.Body weight(WT)was a significant covariable affecting apparent clearance(CL/F).The population typical values of CL/F,apparent volume of distribution(V/F),and absorption rate constant(Ka)were 2.91 L/h,734 L and 0.3 h^(-1),respectively,in the final model.The expression of the model was as follows:CL/F(L·h^(-1))=2.91×(WT/55)0.531,V/F(L)=734,Ka(h^(-1))=0.3(Fixed).The Monte Carlo simulation results showed that the time for TAM concentration to reach a steady state was 6 to 11 weeks.With the same dosage,the lighter the body weight,the longer it took to reach a steady state.For patients weighing less than 70 kg,the optimal dosing regimen was 10 to 30 mg,and for those over 70 kg,it was 20 to 40 mg.Conclusion The PPK model of concentration in depressive patients treated with FLX was successfully established.The fin

关 键 词：氟西汀 总活性成分 群体药动学 血药浓度 基因多态性 

分 类 号：R969.1[医药卫生—药理学]