机构:[1]Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China [2]Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China 医技科室科研平台职能科室呼吸疾病研究室临床流行病与循证医学中心临床研究中心儿科研究所首都医科大学附属北京儿童医院[3]China National Clinical Research Center for Respiratory Diseases, Respiratory Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China 临床科室医技科室职能科室呼吸科临床流行病与循证医学中心临床研究中心首都医科大学附属北京儿童医院[4]Pediatric Research Institute, Children's Hospital of Hebei Province, Shijiazhuang, China [5]Department of Respiratory Diseases, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China [6]Department of Pharmacy, Xingtai People's Hospital, Xintai, China [7]Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China [8]Department of Pediatric Pharmacology and Pharmacogenetics, H?pital Robert Debré, APHP, Paris, France
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.
基金:
National Science Foundation of ChinaNational Natural Science Foundation of China [81703603]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015M582102, 2017M620831]; National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002, 2017ZX09304029-005]; Young Taishan Scholars Program; Fundamental Research Fund [2016GN029]; Capital's Funds for Health Improvement and Research [2016-1-2092]; Young Scholars Program of Shandong University [2015WLJH49]
第一作者机构:[1]Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
共同第一作者:
通讯作者:
通讯机构:[1]Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China [2]Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China [7]Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
推荐引用方式(GB/T 7714):
Zheng Yi,Liu Shu-Ping,Xu Bao-Ping,et al.Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia[J].ANTIMICROBIAL AGENTS AND CHEMOTHERAPY.2018,62(9):-.doi:10.1128/AAC.00686-18.
APA:
Zheng, Yi,Liu, Shu-Ping,Xu, Bao-Ping,Shi, Zhong-Ren,Wang, Kai...&Zhao, Wei.(2018).Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,62,(9)
MLA:
Zheng, Yi,et al."Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 62..9(2018):-