基于新型肾功能标志物的中国儿童万古霉素群体药物动力学模型的建立与给药方案的优化

甲氧西林耐药葡萄球菌（MRS）是我国细菌耐药的突出问题。万古霉素（VAN）是治疗MRS感染的首选药物，但其治疗窗窄，剂量过高引起肾毒性，剂量过低导致治疗失败及耐药的发生。目前VAN在儿童患者中的目标谷浓度和给药方案尚不明确，且儿童肾功能未发育成熟，VAN易在体内蓄积而发生中毒。我们前期的研究建立了中国成人VAN群体药物动力学模型，实现了个体化给药。本项目拟以2岁～18岁儿童为研究群体，利用常规TDM数据，使用NONMEM方法分别建立基于新型肾功能标志物胱抑素C（CysC）和血清肌酐（SCr）的中国儿童VAN群体药物动力学模型，通过贝叶斯反馈法计算患者个体药动学参数，明确儿童患者AUC/MIC ≥ 400时对应的谷浓度范围，通过蒙特卡洛仿真法优化给药方案，并研究VAN谷浓度与临床疗效的关系，寻找治疗失败的危险因素，检测患者尿中肾损伤分子-1（KIM-1）的含量变化探讨VAN对肾功能的影响。

Methicillin resistant Staphylococcus (MRS) is a prominent bacterial resistance issue in China. Vancomycin still remains a primary therapeutic choice against MRS pathogens. However, Vancomycin has a narrow therapeutic range, high doses are associated with nephrotoxicity, low doses cause even treatment failure or the emergence of reduced vancomycin susceptibility. Current the therapeautic target trough concentration and the recommended dosing regimens of vancomycin for pediatric patients is not inadequate. The kidney functions of pediatric patients are not fully mature and vancomycin excretion is low, which lead to vanocmycin accumalate in the body and cause posoning. We previous repoted a vancomycin population pharmacokinetic model for Chinese adult patients, and realized the individual therapy.The aim of our research is to develop two population pharmacokinetic models for chinese pediatric patients (2 to 18 years of age) by using cystatin C (CysC) and serum creatinine (SCr) as significant covariate, respectively; determine the relationship between vancomyicn steady-state trough concentration and AUC0-24h in pediatric patient by Bayesion method, and develop initial dosage regimens using Monte Carlo simulation. Population pharmacokinetic modeling is perfomed in NONMEN. Our research also evaluation the relationship between the vancomycin trough concentration and treatment outcomes and identify specific risk factors for treament failure in pediatric patients. To identity the relationship of vancomycin trough concentration and renal function, the urinary kidney injury molecule-1 (KIM-1) concentration will be measured.