Anderson Brian J, Hannam Jacqueline A
Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.
Department of Pharmacology & Clinical Pharmacology, Auckland University, Auckland, New Zealand.
Paediatr Anaesth. 2019 Nov;29(11):1107-1113. doi: 10.1111/pan.13731. Epub 2019 Sep 25.
Ibuprofen is widely used for ductus arteriosus closure in premature neonates and for analgesia in children and adults. There are no maturation descriptors of clearance. This lack of maturation understanding limits dosing recommendations from premature neonates to adulthood.
Published clearance estimates from different aged patients determined after administration from time-concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed-effects models. A target concentration strategy was used to estimate maintenance dose at different ages.
There were three publications reporting an estimate of individual clearance estimates in premature neonates, three reporting population clearances in infants, 11 in children 2-15 years (1 with individual and 9 with population clearances), and 13 adult studies (1 with individual and 12 with population clearances). Clearance maturation, standardized to a 70 kg person was described using the Hill equation. Mature clearance was 3.81 (CV 15.5%, 95%CI 3.72, 3.92) L/h/70 kg. The maturation half-time was 36.8 (CV 9.2%, 95%CI 34.7, 40.9) weeks postmenstrual age and the Hill coefficient 11.5 (95%CI 8.1, 15). A target effect of four units (visual analogue scale 0-10) correlated with an effect site concentration of 6.3 mg/L: a concentration achieved at trough after 400 mg 8 hourly in adults.
Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. Maturation of ibuprofen clearance was rapid and was 90% of adult values by the first month of life in term neonates (ie, 44 weeks postmenstrual age) and 98% of standardized adult estimates by 3 months of age (53 weeks postmenstrual age). Clearance informed dosing predictions in all ages (premature neonate to adult) and matched those doses in common use in children older than 3 months.
布洛芬广泛用于早产儿动脉导管未闭的治疗以及儿童和成人的镇痛。目前尚无关于清除率的成熟度描述。对清除率成熟度缺乏了解限制了从早产儿到成人的给药建议。
利用从不同年龄患者给药后的时间-浓度曲线确定的已发表清除率估计值，构建基于体重和年龄的成熟度模型。使用非线性混合效应模型进行曲线拟合。采用目标浓度策略估算不同年龄的维持剂量。
有三篇出版物报告了早产儿个体清除率的估计值，三篇报告了婴儿群体清除率，11篇报告了2至15岁儿童的清除率（1篇个体清除率和9篇群体清除率），以及13项成人研究（1篇个体清除率和12篇群体清除率）。以70kg体重的人为标准，使用希尔方程描述清除率成熟度。成熟清除率为3.81（CV 15.5%，95%CI 3.72，3.92）L/h/70kg。成熟半衰期为月经后年龄36.8（CV 9.2%，95%CI 34.7，40.9）周，希尔系数为11.5（95%CI 8.1，15）。四个单位的目标效应（视觉模拟评分0-10）与效应部位浓度6.3mg/L相关：这是成人每8小时服用400mg后谷浓度时达到的浓度。
先前发表的药代动力学参数可用于建立成熟度模型，以填补目前关于年龄对药物处置影响的知识空白。布洛芬清除率成熟迅速，足月新生儿出生后第一个月（即月经后年龄44周）达到成人值的90%，3个月龄（月经后年龄53周）达到标准化成人估计值的98%。清除率为所有年龄段（早产儿到成人）的给药预测提供了依据，并与3个月以上儿童常用剂量相符。
