美罗培南在血液肿瘤患者中的PK/PD研究及PPK模型构建

Pharmacokinetics/Pharmacodynamics Study and Population Pharmacokinetics Model Establishment of Meropenem in Patients with Haematological Malignancies

目的探讨血液肿瘤患者使用美罗培南传统输注方案(1 g,q8h,静脉滴注0.5 h)经验性抗感染能否达到可接受的目标获得概率(PTA);并筛选影响其药动学(PK)参数的协变量,构建群体药动学(PPK)模型,为美罗培南在血液肿瘤患者中合理应用提供理论支持。方法收集2020年12月—2021年6月期间上海交通大学医学院附属第一人民医院使用美罗培南传统输注方案经验性抗感染的血液肿瘤患者29例,每例患者在给药后采集3个点的血药浓度。利用这些稀疏采样数据,借助Phoenix 64版软件采用非线性混合效应法构建PK基础模型,根据该模型输出每例患者的药-时曲线数据,从而计算不同预设药动学/药效学(PK/PD)靶标下的PTA。再采用逐步回归法筛选影响美罗培南PK参数的协变量,构建PPK模型并进行验证。结果只有当美罗培南对致病菌的最低抑菌浓度(MIC)≤1μg·mL^(-1),且预设PK/PD靶标为游离美罗培南药物浓度超过MIC的时间大于给药间隔40%时(40%fT>MIC),PTA才能达到90%以上。协变量筛选显示血清白蛋白的水平影响美罗培南的PK参数,通过纳入该协变量,最终构建的PPK模型拟合较好。结论该院血液肿瘤患者使用美罗培南传统输注策略进行经验性抗感染治疗不能达到很好的效果,需要考虑加大药物剂量或延长输注时间。构建的美罗培南PPK最终模型具有较好的预测能力和稳定性,可以为美罗培南个体化给药方案的制定提供有力依据。

Objective To investigate whether the conventional dosage regimen of meropenem(1 g,q8h,ivgtt for 0.5 h)can achieve the acceptable probability of target attainment(PTA)in patients with hematological malignancies and to screen the covariates affecting pharmacokinetics(PK)parameters of meropenem to establish a population pharmacokinetic(PPK)model then provide theoretic supports for the rational administration of meropenem in patients with hematological malignancies.Methods Twenty-nine patients who were diagnosed with hematological malignancies and received the conventional dosage regimen of meropenem for empirical antibacterial therapy from December 2020 to June 2021 were enrolled.Blood concentrations of meropenem were collected at three-time points after administration in patients.Based on these sparse sampling data,the PK basic model is constructed by a non-linear mixed effect method with Phoenix 64 software.The PTA in different PK/PD targets was calculated according to the concentration-time curve simulated by the PK basic model.Stepwise regression was used to screen the covariates affecting the PK parameters of meropenem,and the final PPK model was constructed by and validated.Results Only when the minimum inhibitory concentration(MIC)of meropenem to pathogens is≤1μg·mL^(-1) and the preset PK/PD target is 40%fT>MIC,the PTA could reach>90%.Covariates screening showed that serum albumin level affects the PK parameters of meropenem,and the final PPK model is adequate after the inclusion of the covariate.Conclusion Experiential treatment with a conventional dosage regimen of meropenem cannot obtain satisfactory effects in patients with hematological malignancies,and it is necessary to consider increasing the dose or extending the infusion time of meropenem.The final PPK model of meropenem constructed in this study has a high correlativity,fine stability,and precise predictability,which can be used to assist physicians in developing individualized regimens for patients.