Li Xue, Qi Hui, Jin Fei, Yao Bu-Fan, Wu Yue-E, Qi Yu-Jie, Kou Chen, Wu Xi-Rong, Luo Xiao-Jing, Shen Yan-Hua, Zheng Xu, Wang Yong-Hong, Xu Fang, Jiao Wei-Wei, Li Jie-Qiong, Xiao Jing, Dong Yi-Ning, Du Bin, Shi Hai-Yan, Xu Bao-Ping, Shen A-Dong, Zhao Wei
Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
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 100045, China.
Eur J Pharm Sci. 2021 Aug 1;163:105868. doi: 10.1016/j.ejps.2021.105868. Epub 2021 May 2.
Ceftazidime is a third-generation cephalosporin with high activity against many pathogens. But the ambiguity and diversity of the dosing regimens in neonates and young infants impair access to effective treatment. Thus, we conducted a population pharmacokinetic study of ceftazidime in this vulnerable population and recommended a model-based dosage regimen to optimize sepsis therapy. Totally 146 neonates and young infants (gestational age (GA): 36-43.4 weeks, postnatal age (PNA): 1-81 days, current weight (CW): 900-4500 g) were enrolled based on inclusion and exclusion criteria. Ceftazidime bloods samples (203) were obtained using the opportunistic sampling strategy and determined by the high-performance liquid chromatography. The population pharmacokinetic-pharmacodynamic analysis was conducted by nonlinear mixed effects model (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic data. Covariate analysis showed the significance of GA, PNA, and CW on developmental pharmacokinetics. Monte Carlo simulation was performed based on above covariates and minimum inhibitory concentration (MIC). In the newborns with PNA ≤ 3 days (MIC=8 mg/L), the dose regimen was 25 mg/kg twice daily (BID). For the newborns with PNA > 3 days (MIC=16 mg/L), the optimal dose was 30 mg/kg three times daily (TID) for those with GA ≤ 37 weeks and 40 mg/kg TID for those with GA > 37 weeks. Overall, on the basis of the developmental population pharmacokinetic-pharmacodynamic analysis covering the whole range of neonates and young infants, the evidence-based ceftazidime dosage regimens were proposed to optimize neonatal early-onset and late-onset sepsis therapy.
头孢他啶是一种对多种病原体具有高活性的第三代头孢菌素。但新生儿和婴幼儿给药方案的不明确性和多样性影响了有效治疗的可及性。因此，我们在这一脆弱人群中开展了一项头孢他啶群体药代动力学研究，并推荐了一种基于模型的给药方案以优化脓毒症治疗。根据纳入和排除标准，共纳入146例新生儿和婴幼儿（胎龄（GA）：36 - 43.4周，出生后年龄（PNA）：1 - 81天，当前体重（CW）：900 - 4500 g）。采用机会性抽样策略获取头孢他啶血样（203份），并通过高效液相色谱法进行测定。采用非线性混合效应模型（NONMEM）进行群体药代动力学 - 药效学分析。具有一级消除的单室模型能最好地描述药代动力学数据。协变量分析显示GA、PNA和CW对发育药代动力学具有显著意义。基于上述协变量和最低抑菌浓度（MIC）进行蒙特卡洛模拟。在PNA≤3天的新生儿中（MIC = 8 mg/L），给药方案为每日两次（BID），每次25 mg/kg。对于PNA>3天的新生儿（MIC = 16 mg/L），GA≤37周者的最佳剂量为每日三次（TID），每次30 mg/kg；GA>37周者的最佳剂量为每日三次（TID），每次40 mg/kg。总体而言，在涵盖整个新生儿和婴幼儿范围的发育群体药代动力学 - 药效学分析基础上，提出了基于循证的头孢他啶给药方案以优化新生儿早发型和晚发型脓毒症治疗。
