Supplementary Material for: Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2–5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9–2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.

背景：苯巴比妥和咪达唑仑是治疗（近）足月新生儿缺氧缺血性脑病时，接受治疗性降温、镇静以及作为抗癫痫药物中常用的药物。苯巴比妥是细胞色素P450（CYP）3A的诱导剂，而咪达唑仑则是CYP3A的底物。因此，苯巴比妥的联合用药可能会影响咪达唑仑的清除率。目标：评估苯巴比妥和咪达唑仑在窒息新生儿中的药代动力学和临床抗癫痫疗效，并制定剂量指南。方法：数据收集于前瞻性多中心PharmaCool研究。在本研究中，接受治疗性降温并接受咪达唑仑和/或苯巴比妥治疗的足月新生儿被纳入研究。在出生后第2-5天采集的血液样本中，测定了苯巴比妥和咪达唑仑及其代谢物的血浆浓度。采用非线性混合效应模型进行药代动力学分析；临床疗效定义为无需额外使用抗癫痫药物。结果：113名（苯巴比妥）和118名（咪达唑仑）新生儿的资料可用；68名新生儿接受了两种药物的联合治疗。仅1-羟基咪达唑仑的清除率受降温影响。苯巴比妥的联合应用使咪达唑仑的清除率提高了2.3倍（95% CI 1.9-2.9，p < 0.05）。抗惊厥疗效为苯巴比妥65.5%，咪达唑仑辅助用药为37.1%。结论：治疗性降温不影响（近）足月新生儿缺氧缺血性脑病患者的苯巴比妥或咪达唑仑的清除率。建议苯巴比妥剂量为30 mg/kg以达到治疗浓度。苯巴比妥的联合应用显著提高了咪达唑仑的清除率。如将苯巴比妥替换为非CYP3A诱导剂的抗惊厥一线治疗药物，可能需要将咪达唑仑的维持剂量降低50%，以避免出生后初期过度暴露。