肾移植患者霉酚酸暴露量的影响因素分析及其对血液系统不良反应的预测价值

Analysis of factors influencing mycophenolic acid exposure in kidney transplant recipients and its predictive value for hematologic adverse effects

目的:研究麦考酚钠肠溶片(enteric-coated mycophenolate sodium,EC-MPS)在肾移植患者体内的药动学特征,分析影响其活性成分霉酚酸(mycophenolic acid,MPA)暴露量的临床因素以及MPA暴露量对血液系统不良反应的预测价值。方法:纳入2016年5月至2019年1月于南京医科大学第一附属医院行同种异体肾移植手术或术后常规随访的164例成人患者,采用“EC-MPS+他克莫司+糖皮质激素”免疫抑制方案。采用酶增强免疫分析技术测定MPA浓度,非房室模型计算药动学参数,梯形法计算MPA AUC。采用单因素方差分析、多元线性回归等方法对MPA暴露量与临床变量的相关性进行分析,采用受试者工作特征曲线计算截断值。结果:EC-MPS药动学符合肠溶片的吸收特点,平均MPA AUC为(76.53±28.64)mg·h·L^(-1),在目标范围内的比例为40.24%。白蛋白水平与MPA暴露量呈显著正相关,而白细胞水平则与其呈显著负相关。白蛋白水平、MPA AUC预测MPA暴露不足和白细胞减少的界值分别为39.5 g·L^(-1)和126.3 mg·h·L^(-1)。结论:服用EC-MPS的肾移植患者MPA AUC达标率较低,建议进行MPA血药浓度监测。白蛋白水平降低时应注意调整给药剂量,同时避免MPA暴露量过高,以降低白细胞减少等不良反应的发生率。

OBJECTIVE To investigate the pharmacokinetic properties of enteric-coated mycophenolate sodium(EC-MPS)in kidney transplant recipients,and to analyze the clinical factors influencing mycophenolic acid(MPA)exposure,as well as the predictive value of MPA exposure for hematological adverse reactions.METHODS From May 2016 to January 2019,a total of 164 patients who underwent kidney transplantation or followed up in The First Affiliated Hospital of Nanjing Medical University and were treated with EC-MPS,tacrolimus and prednisone for immunosuppressive therapy were included in this study.Enzyme-multiplied immunoassay technique assay was used for the MPA concentration determination,non-compartment analysis was utilized to obtain the EC-MPS pharmacokinetic parameters,and trapezoidal method was applied to calculating AUC0-12 h of MPA.The correlation between the clinical variables and MPA exposure was assessed by one-way ANOVA and multiple linear regression,while receiver operating characteristic curve was utilized to determine the cut-off value.RESULTS The pharmacokinetics of EC-MPS was consistent with the absorption characteristics of enteric-coated tablets.The average AUC0-12 h was(76.53±28.64)mg·h·L^(-1),and the proportion within the therapeutic range was 40.24%.The albumin levels exhibited a significant positive correlation with the MPA exposure,while the white blood cell levels demonstrated a significant negative correlation.The albumin level and AUC thresholds of MPA for predicting MPA underexposure and leukopenia were determined to be 39.5 g·L^(-1) and 126.3 mg·h·L^(-1),respectively.CONCLUSION Kidney transplant recipients treated with EC-MPS exhibit suboptimal achievement of the MPA exposure target.Therefore,it is necessary to monitor the concentration of MPA.Dose adjustments should be made when albumin levels decrease,while avoiding excessive MPA exposure to reduce the incidence of adverse reactions such as leukopenia.