Hirt Déborah, Van Overmeire Bart, Treluyer Jean-Marc, Langhendries Jean-Paul, Marguglio Arnaud, Eisinger Mark J, Schepens Paul, Urien Saïk
EA3620, Université Paris - Descartes, Paris, France.
Br J Clin Pharmacol. 2008 May;65(5):629-36. doi: 10.1111/j.1365-2125.2008.03118.x. Epub 2008 Feb 27.
Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.
A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.
Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.
Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.
To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.
布洛芬是一种非甾体抗炎药，可促使新生儿动脉导管闭合。对布洛芬药代动力学的研究较少，且仅限于一小部分早产儿，研究显示个体间差异很大，且清除率随出生后年龄或胎龄增加。
对66例新生儿进行了群体药代动力学研究，以描述布洛芬的浓度-时间过程。布洛芬清除率从出生后第1天到第8天显著增加，但与胎龄无关。研究显示布洛芬曲线下面积（AUC）与动脉导管闭合率之间存在关联，并证实了有效阈值AUC。根据出生后年龄提出了给药方案，以达到该AUC并提高新生儿动脉导管未闭的治疗效果。目的是描述布洛芬在患有动脉导管未闭（PDA）的早产儿中的药代动力学，并建立剂量、血浆浓度与布洛芬疗效及安全性之间的关系。
66例新生儿连续3天静脉输注布洛芬赖氨酸，中位日剂量分别为10、5和5mg/kg。使用NONMEM建立群体药代动力学模型。采用贝叶斯个体药代动力学估计值计算曲线下面积（AUC）并模拟剂量。对PDA闭合情况进行逻辑回归分析。
布洛芬药代动力学可用具有线性消除的一室模型描述。群体药代动力学平均估计值及相应的个体间变异系数（%）为：消除清除率CL = 9.49ml/h（62%），分布容积V = 375ml（72%）。布洛芬CL随出生后年龄（PNA）显著增加：CL = 9.49×(PNA/96.3)^(1.49)。57例PDA闭合的新生儿首剂后AUC（AUC1D）、三剂后AUC总和（AUC3D）及胎龄显著高于9例PDA未闭合的新生儿（P = 0.）。当AUC1D < 600mg·l^(-1)·h（或AUC3D < 900mg·l^(-1)·h）时，50%的新生儿PDA闭合；当AUC1D > 600mg·l^(-1)·h（或AUC < 900mg·l^(-1)·h）时，91%的新生儿PDA闭合（P = 0.006）。未发现AUC与副作用之间存在相关性。
为达到这些最佳AUC，无论胎龄如何，建议对小于70小时的新生儿每24小时间隔给药3次，剂量为10、5、5mg/kg；对70至108小时的新生儿为14、7、7mg/kg；对108至180小时的新生儿为18、9、9mg/kg。
