Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia
Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia
复制标题
阿奇霉素在社区获得性肺炎儿童中的群体药代动力学和剂量优化
DOI：
10.1128/aac.00686-18
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Wei Zhao
中科院分区：
文献类型：
--
作者：
Yi Zheng;Shu-Ping Liu;Bao-Ping Xu;Zhong-Ren Shi;Kai Wang;Jin-Bin Yang;Xin Huang;Bo-Hao Tang;Xing-Kai Chen;Hai-Yan Shi;Yue Zhou;Yue-E Wu;Hui-Qi;Evelyne Jacqz-Aigrain;A-Dong Shen;Wei Zhao
阿奇霉素广泛用于儿童社区获得性肺炎（CAP）。目前，静脉注射阿奇霉素在儿童中被超说明书使用，部分原因是缺乏药代动力学数据。摘要阿奇霉素广泛应用于儿童社区获得性肺炎（CAP）的治疗。目前，静脉注射阿奇霉素在儿童中被超说明书使用，部分原因是缺乏药代动力学数据。我们的目的是评估群体药代动力学（PPK）和优化剂量策略，以改善这一独特人群的治疗。这是一项前瞻性、多中心、开放标签药代动力学研究。从住院儿科患者中采集血液样本，并通过液相色谱-串联质谱法（LC-MS/MS）测定浓度。使用NONMEM软件进行PPK分析。95例儿科患者（年龄范围：2.1 - 11.7岁）的药代动力学数据可用于分析。PPK最佳拟合为线性消除的二室模型。协变量分析证实，体重和丙氨酸氨基转移酶（ALT）对阿奇霉素的药代动力学有显著影响，ALT>40的患者清除率降低24%。蒙特卡罗模拟表明，对于肝功能正常的儿童，（负荷剂量为15 mg/kg体重，随后维持剂量为10 mg/kg）将达到24 h内游离药物血浆浓度-时间曲线下面积（fAUC）与MIC 90的比值在53.2%的假设患者中，使用2 mg/L的标准MIC敏感性断点，3 h的fAUC/MIC目标。对于ALT>40的儿童，建议的剂量需要减少15%才能达到相当的暴露量。推荐给药方案的相应药物过量风险低于5.8%。总之，评估了阿奇霉素在CAP儿童中的PPK，并基于发育药代动力学-药效学建模和模拟构建了最佳给药方案。
Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. ABSTRACT Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.
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影响因子：
6.1
作者：
Comets, Emmanuelle;Brendel, Karl;Mentre, France
通讯作者：
Mentre, France
影响因子：
1.8
作者：
Legrand, Tiphaine;Elie, Valery;Pruvost, Alain
通讯作者：
Pruvost, Alain
影响因子：
1.8
作者：
G. Drusano;W. Craig
通讯作者：
G. Drusano;W. Craig
DOI：
10.1001/jama.2015.13896
发表时间：
2015-11-17
期刊：
JAMA
影响因子：
--
作者：
Bacharier LB;Guilbert TW;Mauger DT;Boehmer S;Beigelman A;Fitzpatrick AM;Jackson DJ;Baxi SN;Benson M;Burnham CD;Cabana M;Castro M;Chmiel JF;Covar R;Daines M;Gaffin JM;Gentile DA;Holguin F;Israel E;Kelly HW;Lazarus SC;Lemanske RF Jr;Ly N;Meade K;Morgan W;Moy J;Olin T;Peters SP;Phipatanakul W;Pongracic JA;Raissy HH;Ross K;Sheehan WJ;Sorkness C;Szefler SJ;Teague WG;Thyne S;Martinez FD
通讯作者：
Martinez FD
影响因子：
4.9
作者：
Deshpande, Devyani;Pasipanodya, Jotam G.;Gumbo, Tawanda
通讯作者：
Gumbo, Tawanda