Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Antimicrob Agents Chemother. 2019 Jan 29;63(2). doi: 10.1128/AAC.02336-18. Print 2019 Feb.
Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.
阿莫西林被广泛用于治疗新生儿的细菌感染。然而，在临床实践中，抗生素的剂量方案存在相当大的中心间变异性。阿莫西林的药代动力学仅在少数早产儿中进行了描述。因此，我们旨在通过涵盖新生儿和婴儿整个年龄段的大样本量来评估阿莫西林的群体药代动力学，并基于发育药代动力学-药效学建立基于证据的剂量方案。这是一项使用机会性采样设计的前瞻性、多中心药代动力学研究。使用高效液相色谱法测定阿莫西林的血浆浓度。使用 NONMEM 进行群体药代动力学分析。共 187 名新生儿（胎龄范围 28.4 至 46.3 周）的 224 个药代动力学样本可用于分析。采用一阶消除的两室模型来描述群体药代动力学。协变量分析表明，当前体重、出生后年龄和胎龄是重要的协变量。最终模型在患者的独立队列中进一步验证了预测性能。蒙特卡罗模拟表明，对于早发性败血症，目前使用的剂量方案（25mg/kg 每日两次 [BID]）导致 99.0%的早产儿和 87.3%的足月儿达到药效学目标（MIC 以上时间百分比），MIC 断点为 1mg/L。对于晚发性败血症，25mg/kg 每日三次（TID）治疗的早产儿中有 86.1%和接受 25mg/kg 每日四次（QID）的足月儿中有 79.0%达到药效学目标，MIC 断点为 2mg/L。评估了新生儿和婴儿的阿莫西林群体药代动力学。根据发育药代动力学-药效学建立了剂量方案。
