Chen Yewei, Sun Li, Xu Hong, Dong Min, Mizuno Tomoyuki, Vinks Alexander A, Brunner Hermine I, Li Yifan, Li Zhiping
Department of Pharmacy, Children's Hospital of Fudan University, Shanghai, China.
Division of Rheumatology, Children's Hospital of Fudan University, Shanghai, China.
Front Pharmacol. 2020 Dec 21;11:605060. doi: 10.3389/fphar.2020.605060. eCollection 2020.
To evaluate the mycophenolic acid [MPA, the active form of mycophenolate mofetil (MMF)] pharmacokinetic parameters in relation to clinical response to identify target exposure ranges in pediatric patients with systemic lupus erythematosus (SLE). This was a retrospective study using pharmacokinetic data collected in 67 pediatric patients aged 4-18 years with SLE. Target MPA exposures for effective inhibition of SLE activity (as measured by SLE disease Activity Index (SLEDAI), active SLE was defined as a SLEDAI score of ≥6, and a controlled disease was defined as a SLEDAI score of ≤4) were assessed by receiver operating characteristic (ROC) curve and logistic regression. Exposure-response models were developed to quantitatively describe the relationship between SLEDAI score and AUC or C, respectively. The MPA AUC in patients with active SLE was significantly lower than that in patients with inactive SLE. ROC analysis revealed that an AUC threshold of 39 μg h/ml or a C of 1.01 μg/ml was associated with the lowest risk of active SLE. Logistic regression analysis revealed that an AUC of less than 34 μg h/ml or a C of less than 1.2 μg/ml probably is associated with active SLE. The results of the exposure-response modeling also indicated that an AUC less than 32 μg h/ml or a C less than 1.1 μg/ml was associated with suboptimal clinical outcome. An AUC above 50 μg h/ml or a C above 1.7 ug/ml was associated with disease control. Both AUC and C of MPA are predictive of the likelihood of active SLE in pediatric patients receiving MMF. An individualized dosing regimen of MMF, with a target AUC or C, should be considered for SLE patients.
评估霉酚酸[MPA，霉酚酸酯（MMF）的活性形式]的药代动力学参数与临床反应的关系，以确定系统性红斑狼疮（SLE）患儿的目标暴露范围。这是一项回顾性研究，使用了收集的67例4至18岁SLE患儿的药代动力学数据。通过受试者工作特征（ROC）曲线和逻辑回归评估有效抑制SLE活动（通过SLE疾病活动指数（SLEDAI）衡量，活动性SLE定义为SLEDAI评分≥6，疾病得到控制定义为SLEDAI评分≤4）的目标MPA暴露量。建立暴露-反应模型以分别定量描述SLEDAI评分与AUC或C之间的关系。活动性SLE患者的MPA AUC显著低于非活动性SLE患者。ROC分析显示，AUC阈值为39μg·h/ml或C为1.01μg/ml与活动性SLE的最低风险相关。逻辑回归分析显示，AUC小于34μg·h/ml或C小于1.2μg/ml可能与活动性SLE相关。暴露-反应模型的结果还表明，AUC小于32μg·h/ml或C小于1.1μg/ml与临床结局欠佳相关。AUC高于50μg·h/ml或C高于1.7μg/ml与疾病得到控制相关。MPA的AUC和C均能预测接受MMF治疗的SLE患儿发生活动性SLE的可能性。对于SLE患者，应考虑采用具有目标AUC或C的MMF个体化给药方案。
