去甲万古霉素群体药代动力学与药效学分析及给药方案的优化

A study on the population pharmacokinetics and pharmacodynamics with an optimized dose regime of norvancomycin

目的了解去甲万古霉素在感染患者中群体药代动力学(PPK)和药效学(PD)。方法药代动力学(PK)分析在诊断或拟诊为革兰阳性菌感染的146例患者中进行,收集患者的临床资料,以NONMEM程序建立并验证去甲万古霉素PK模型。PD分析在同组感染者中进行,收集病原菌,以琼脂对倍稀释法测定去甲万古霉素对细菌最低抑菌浓度(MIC)。根据患者的PK参数和MIC测定结果,计算患者的PK/PD参数,分析其与去甲万古霉素临床和细菌学疗效的关系,制定最佳给药方案。结果去甲万古霉素基础PK模型为线性二房室模型,PK参数个体间变异为指数模型,个体内变异为加法模型。患者内生肌酐清除率(Ccr)的变化对去甲万古霉素清除率(CL)的影响不同,当患者肾功能减退时(Ccr≤85mL/min),CL=2.54×(Ccr/50)^(1.20),Ccr的变化影响该药在体内清除速率,当患者肾功能正常时(Ccr>85 mL/min),CL=5.66×(体质量/60)^(0.52),患者Ccr的变化并不影响药物的廓清率。患者合并使用利尿剂后,去甲万古霉素周边室分布容积(V_2)增大。CL、中央室分布容积(V_1)、室间清除率(Q)和V_2的患者个体间变异分别为35.92%、11.40%、0和79.75%,残差误差为3.05 mg/L。葡萄球菌及肠球菌感染者经去甲万古霉素治疗后治愈组和未治愈组比较,在葡萄球菌感染苦中两组间给药剂量、年龄、药时曲线下面积(AUC)_(24)和AUC_(24)/MIC的差异具有统计学意义(P<0.05)。肠球菌感染者两组间AUC_(24)和AUC_(24)/MIC的差异亦具有统计学意义(P<0.05)。多因素回归分析显示,仅AUC_(24)/MIC是影响治愈率的因素。当葡萄球菌感染组和肠球菌感染组的AUC_(24)/MIC平均值分别为579.90和637.67时,去甲万古霉素对患者的治愈率可达95%。结论AUC_(24)/MIC可作为去甲万古霉素治疗耐药革兰阳性菌感染时预测临床和细菌学疗效的指标,据此制定适用于不同感染患者群体的最佳给药方案。

Objective To investigate population pharmcokinetics（PPK）and pharmacodynamics （PD）of norvancomycin in patients. Methods The pharmcokinetics（PK） study was performed in 146 patients confirmed and suspected with gram positive bacterial infections whose clinical data were also collected. A PPK model was developed and validated by the NONMEM software. The PD study was performed in the same patients. The norvancomycin minimal inhibitory concentrations（MIC） of clinically isolated strains were determined by agar dilution methods. The PK/PD profiles resulted from the PK parameters in the patients and from MIC values. An optimal dose regime was derived from the analyses of the PK/PD model relevant to the clinical and bacterial relationships. Results The basic PK model of norvancomycin was a linear two compartmental model with exponential interindividual variability and additive residual error statistical models. The change of creatinine clearance（Ccr） values had different impacts on drug clearance （CL）. When patients had renal dysfunction （Ccr≤85 mL/min）, CL （Liters/h） 2.54 · （Cer/50）1-20 , the clearance of the drug was influenced by different Cer. But when patients had normal renal function （Ccr〉85 mL/min）, CL= 5. 66 · （body weight/60）0.52 it wasn＇t influenced. The increased volume of a peripheral distribution （V2） was observed when norvaneomycin was co-administered with diuretics. Interindividual variability in CL, V1 , Q and V2 was 35.92%, 11.40% 0 and 79.75%, respectively. Residual variability was 3.05 mg/L. Patients with Staphylococcus aureus infection and Enterococcal infection were divided into two groups： norvancomycin cured group and uncured group. The dosage, age, area under the curve（AUC）24 and AUC2t/MIC of patients with Staphylococcus aureus infection were significantly different in two groups （P 〈 0.05）. On the other hand, AUC24 and AUC24/MIC of patients with Enterococcal infection were significantly different in two groups （ P 〈 0.05）. The Logistic stepwise analysis revealed that only AUC24/MIC was the major factor which could significantly affect the clinical outcomes. If AUC24/MIC of patients with Staphylococcus aureus infection and enterococcal infection were 579.90 and 637.67, respectively, the cured rate of norvancomycin was up to 95%. Conclusions AUC24/MIC can be a predictor of clinical and bacterial outcomes in norvancomycin treated drug-reslstant gram-positive bacterial infections. An optimized regimen of norvancomycin can be simulated and developed for different subgroups of patients who have special physiologic and pathologic conditions.