Padavia Faheemah, Treluyer Jean-Marc, Cambonie Gilles, Flamant Cyril, Rideau Aline, Tauzin Manon, Patkai Juliana, Gascoin Géraldine, Lumia Mirka, Aikio Outi, Foissac Frantz, Urien Saïk, Benaboud Sihem, Lui Gabrielle, Froelicher Bournaud Léo, Zheng Yi, Kemper Ruth, Tortigue Marine, Baruteau Alban-Elouen, Kallio Jaana, Hallman Mikko, Diallo Alpha, Levoyer Léa, Roze Jean-Christophe, Bouazza Naïm
Université Paris Cité, Inserm, Pharmacologie et évaluation des thérapeutiques chez l'enfant et la femme enceinte, 75006, Paris, France.
Unité de Recherche Clinique Necker-Cochin, AP-HP, Hôpital Tarnier, Paris, France.
Clin Pharmacokinet. 2025 Sep 1. doi: 10.1007/s40262-025-01567-4.
Patent ductus arteriosus is a common complication of extreme prematurity. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing mortality and morbidity. Prophylactic treatment by paracetamol could be a safer alternative.
The aim was to build a pharmacokinetic-pharmacodynamic (PKPD) model describing the effect of paracetamol on the time-course of the ductus arteriosus diameter.
Extremely preterm neonates of 23-26 weeks of gestational age were recruited within 12 h after birth and were treated with prophylactic intravenous paracetamol for 5 days (two dose levels: 20 mg/kg followed by 7.5 mg/kg or 25 mg/kg followed by 10 mg/kg every 6 h). The diameter of ductus arteriosus was determined by echocardiography performed daily until day 7. The PKPD model was built using an I model with effect compartment and exponential disease progression model. Concentrations of paracetamol in the effect compartment were simulated with different doses over time for 500 virtual patients.
A total of 29 extremely preterm neonates with median birth weight of 800 g (IQR: 670-860) were included in the study. Between-subject variability was estimated on transfer rate constant between the central compartment and the effect compartment (ke) and maximum drug inhibition (I) parameters. Two subpopulations with different I values were identified: 99% for a first subpopulation of 10 patients and 42% for the second subpopulation of 19 patients. A negative effect of maximum fraction of inspired oxygen (FiO) used during transfer to intensive care unit and a positive effect of intubation and ventilation during treatment were significant on ke. Simulations showed that both dose levels generally enabled patients to reach the concentration needed to achieve 95% of maximal inhibition by the end of treatment. However, the second dose level enabled more than 90% of patients to reach this inhibition threshold as early as day one.
The relationship between paracetamol and the time-course of ductus arteriosus diameter has been described in extremely preterm neonates. Intravenous paracetamol treatment with a loading dose of 25 mg/kg within 12 h after birth followed by 10 mg/kg every 6 h appears to be effective to accelerate time to ductus closure with limited benefit of a further dose increase.
动脉导管未闭是极早产儿常见的并发症。吲哚美辛或布洛芬预防性治疗已显示出对动脉导管闭合有效，但并未降低死亡率和发病率。对乙酰氨基酚预防性治疗可能是一种更安全的选择。
旨在建立一个药代动力学-药效学（PKPD）模型，描述对乙酰氨基酚对动脉导管直径随时间变化的影响。
招募出生后12小时内胎龄23 - 26周的极早产儿，给予预防性静脉注射对乙酰氨基酚5天（两个剂量水平：20mg/kg，随后每6小时7.5mg/kg；或25mg/kg，随后每6小时10mg/kg）。每天通过超声心动图测定动脉导管直径直至第7天。使用带有效应室的I模型和指数疾病进展模型建立PKPD模型。对500名虚拟患者随时间用不同剂量模拟效应室内对乙酰氨基酚的浓度。
共纳入29例极早产儿，中位出生体重800g（四分位间距：670 - 860）。对中央室与效应室之间的转运速率常数（ke）和最大药物抑制（I）参数估计了个体间变异性。确定了两个具有不同I值的亚组：10例患者的第一个亚组为99%，1例患者的第二个亚组为42%。转运至重症监护病房期间使用的最大吸入氧分数（FiO）有负面影响，治疗期间插管和通气有正面影响，对ke有显著意义。模拟显示，两个剂量水平通常使患者在治疗结束时达到实现最大抑制95%所需的浓度。然而，第二个剂量水平使超过90%的患者早在第1天就达到该抑制阈值。
已描述了对乙酰氨基酚与极早产儿动脉导管直径随时间变化的关系。出生后12小时内静脉注射对乙酰氨基酚负荷剂量25mg/kg，随后每6小时10mg/kg，似乎能有效加速动脉导管闭合时间，进一步增加剂量获益有限。
