Kimura Toshimi, Sunakawa Keisuke, Matsuura Nobuo, Kubo Hiroaki, Shimada Shigehiko, Yago Kazuo
Department of Pharmacy, Kitasato University Hospital, 1-15-1 Kitasato, Sagamihara-shi, Kanagawa 228-8555, Japan.
Antimicrob Agents Chemother. 2004 Apr;48(4):1159-67. doi: 10.1128/AAC.48.4.1159-1167.2004.
Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL(arbekacin) = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL(arbekacin) = 0.0367 x BW/serum creatinine level for PCAs of > or = 33 weeks, V(arbekacin) = 0.54 liters/kg, CL(vancomycin) = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL(vancomycin) = 0.0323 x BW/serum creatinine level for PCAs of > or = 34 weeks, V(vancomycin) = 0.66 liters/kg, CL(panipenem) = 0.0832 for PCAs of <33 weeks and CL(panipenem) = 0.179 x BW for PCAs of > or = 33 weeks, and V(panipenem) = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of > or = 33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.
新生儿不成熟的肾功能需要调整抗生素剂量。进行了群体药代动力学研究，以确定三种抗生素的最佳给药方案：一种氨基糖苷类抗生素阿贝卡星、一种糖肽类抗生素万古霉素和一种碳青霉烯类抗生素帕尼培南。83例新生儿接受了阿贝卡星（n = 41）、万古霉素（n = 19）或帕尼培南（n = 23）治疗。孕龄（PCA）为24.1至48.4周，体重（BW）范围为458至5200 g。应用具有一级消除的一室开放模型，并使用非线性混合效应模型进行群体药代动力学分析评估。在拟合过程中，与清除率（CL）显著相关的固定效应因素为PCA、出生后年龄、胎龄、BW和血清肌酐水平；与分布容积（V）显著相关的固定效应因素为BW。群体药代动力学参数的最终公式如下：对于PCA<33周的阿贝卡星，CL(阿贝卡星)=0.0238×BW/血清肌酐水平；对于PCA≥33周的阿贝卡星，CL(阿贝卡星)=0.0367×BW/血清肌酐水平；V(阿贝卡星)=0.54升/千克；对于PCA<34周的万古霉素，CL(万古霉素)=0.0250×BW/血清肌酐水平；对于PCA≥34周的万古霉素，CL(万古霉素)=0.0323×BW/血清肌酐水平；V(万古霉素)=0.66升/千克；对于PCA<33周的帕尼培南，CL(帕尼培南)=0.0832；对于PCA≥33周的帕尼培南，CL(帕尼培南)=0.179×BW；V(帕尼培南)=0.53升/千克。当通过非线性混合效应模型评估每种药物的CL时，我们发现PCA<33至34周的受试者的平均CL显著低于PCA≥33至34周的受试者，并且CL随PCA呈指数增加。许多抗生素通过肾小球滤过排泄，肾小球滤过的成熟是估计抗生素清除率的最重要因素。临床医生在确定新生儿初始抗生素给药方案时应考虑PCA、血清肌酐水平、BW和化学特性。
