Abstract：
OBJECTIVE: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients.
METHODS: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA).
RESULTS: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months).
CONCLUSIONS: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).
METHODS: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA).
RESULTS: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months).
CONCLUSIONS: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).
摘要：
目的：美罗培南/伐巴坦联合用药已被FDA和EMA批准用于成人复杂的尿路感染，EMA也被批准用于其他革兰氏阴性感染。我们旨在在正在进行的儿童研究中表征这两个部分的药代动力学，并使用基于模型的方法为儿科患者提供适当的给药方案。
方法：成人超过4196份美罗培南和伐巴坦血样（n=414名受试者），连同年龄在3个月至18岁的儿科患者的114份血液样本(n=39)可用于本分析.使用具有来自成人药代动力学模型的先验信息的人群分析数据，以告知儿童的参数估计。进行模拟以评估不同给药方案实现目标(PTA)的适当概率的适合性。
结果：美罗培南/vaborbactamPK用具有一阶消除的两室模型进行了描述。体重和CLcr是两种药物处置的重要协变量。评估了成熟功能以探索新生儿清除率的变化。对于年龄≥3个月的儿童，在静脉输注美罗培南和vaborbactam的40mg/kgQ8h以及≥50kg的2g/2g后，得出PTA≥90％。配置参数的外推表明，新生儿和婴儿（3个月）在静脉输注20mg/kg3.5小时后即可获得足够的PTA。
结论：对成人和儿科数据的综合分析可以准确描述儿科患者中稀疏地采样的美罗培南/伐巴坦PK，并为新生儿和婴儿（3个月）的给药提供建议。
方法：成人超过4196份美罗培南和伐巴坦血样（n=414名受试者），连同年龄在3个月至18岁的儿科患者的114份血液样本(n=39)可用于本分析.使用具有来自成人药代动力学模型的先验信息的人群分析数据，以告知儿童的参数估计。进行模拟以评估不同给药方案实现目标(PTA)的适当概率的适合性。
结果：美罗培南/vaborbactamPK用具有一阶消除的两室模型进行了描述。体重和CLcr是两种药物处置的重要协变量。评估了成熟功能以探索新生儿清除率的变化。对于年龄≥3个月的儿童，在静脉输注美罗培南和vaborbactam的40mg/kgQ8h以及≥50kg的2g/2g后，得出PTA≥90％。配置参数的外推表明，新生儿和婴儿（3个月）在静脉输注20mg/kg3.5小时后即可获得足够的PTA。
结论：对成人和儿科数据的综合分析可以准确描述儿科患者中稀疏地采样的美罗培南/伐巴坦PK，并为新生儿和婴儿（3个月）的给药提供建议。
