利奈唑胺成人药动学数据在儿童群体中的外推及暴露量-疗效关系研究

目的：本研究拟将成人利奈唑胺群体药动学（PPK）模型和药动学参数外推至儿童，并应用外推模型考察利奈唑胺在儿童群体中的暴露量-效应关系，为重症感染患儿的个体化给药方案制定提供理论依据。方法：选取2015年2月至2018年2月MRSA感染的肺炎患儿60例为研究对象，给予常规剂量利奈唑胺静脉滴注治疗，比较治疗前后患儿的临床症状、实验室检查和影像学检查变化以评价临床疗效；以患儿药动学数据对成人利奈唑胺PPK模型进行校正，计算患儿个体药动学参数并验证外推模型的预测性能；应用ROC曲线分析AUC_0-24h/MIC、C_min与疗效的关系，根据AUC_0-24h/MIC的最佳切点值将患儿分为两组，比较两组患儿的治疗有效率和肺部感染评分（CPIS），评价最佳切点值对疗效预测的意义。结果：外推模型公式对儿童群体药动学参数的预测性能良好；AUC_0-24h/MIC作为疗效预测指标的准确性比C_min更高（AUC_ROC>0.8，P<0.05），且最佳切点值为AUC_0-24h/MIC=95；治疗结束后，AUC_0-24h/MIC ≥ 95组治疗总有效率显著高于AUC_0-24h/MIC<95组（91.30%vs 35.71%，P<0.05）；AUC_0-24h/MIC ≥ 95组的CPIS评分显著低于AUC_0-24h/MIC<95组（2.87±1.87 vs 4.86±1.10，P<0.05）。结论：成人利奈唑胺PPK模型可成功外推至儿童群体并应用于药物暴露-效应关系的考察，在抗菌治疗过程中维持AUC_0-24h/MIC ≥ 95对于获取最佳疗效具有重要意义。

Extrapolation of adult pharmacokinetic data of linezolid in pediatric patients and research onrelationship between drug exposure and efficacy

OBJECTIVE Our research intended to extrapolate population pharmacokinetic(PPK) model and pharmacokinetic parameters from adults to children,and apply extrapolation model to investigate the exposure-response relationship of linezolid in children, so as to provide theoretical basis for individualized drug administration in children with severe infections. METHODS A total of 60 children with MRSA pneumonia who were treated in the hospital from Feb 2015 to Feb 2018 were included and treated with intravenous infusion of conventional dose of linezolid. Changes in clinical symptoms, laboratory tests and imaging examinations before and after treatment were observed and compared to evaluate the clinical efficacy. Pharmacokinetic data of children were used to adjust the PPK model of adults and pharmacokinetic parameters of each child were calculated, then the predictive performance of extrapolation model was tested. ROC curves were used to analyze the relationship between AUC_0-24h/MIC, C_min and efficacy. All children were divided into two groups according to appropriate cut-off value of AUC_0-24h/MIC, the effective rate of clinical treatment and clinical pulmonary infection scores(CPIS)between the two groups of children were compared to assess the importance of cut-off value for prediction of efficacy. RESULTS The extrapolation model showed high predictive performance. Prediction accuracy of AUC_0-24h/MIC in clinical efficacy was better than that of C_min(AUC_ROC>0.8,P<0.05). The appropriate cut-off value of AUC_0-24h/MIC was 95. After the treatment, the effective rate of clinical treatment of AUC_0-24h/MIC ≥ 95 group was significantly higher than that of AUC_0-24h/MIC<95 group(91.30% vs 35.71%,P<0.05), and the CPIS of AUC_0-24h/MIC ≥ 95 group was significantly lower than that of AUC_0-24h/MIC<95 group(2.87±1.87 vs 4.86±1.10,P<0.05). CONCLUSION PPK model of linezolid could be extrapolated successfully from adults to children and the extrapolation model could be applied to investigate the relationship between drug exposure and effect. Maintaining AUC_0-24h/MIC ≥ 95 during antimicrobial therapy is important for obtaining the best efficacy.