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

<b><i>Background:</i></b> 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. <b><i>Objectives:</i></b> To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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, <i>p</i> &lt; 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. <b><i>Conclusions:</i></b> 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.<b><i>背景：</i></b> 苯巴比妥与咪达唑仑是接受治疗性低温（therapeutic hypothermia）治疗的足月儿及近足月儿缺氧缺血性脑病（hypoxic-ischaemic encephalopathy）患儿的常用药物，可用于镇静及/或抗癫痫治疗。苯巴比妥为细胞色素P450（cytochrome P450, CYP）3A的诱导剂，而咪达唑仑属于CYP3A底物，因此二者联合给药可能会影响咪达唑仑的清除率。<b><i>研究目标：</i></b> 评估缺氧窒息新生儿联合使用苯巴比妥与咪达唑仑的药代动力学特征及临床抗癫痫疗效，并制定给药方案指南。<b><i>研究方法：</i></b> 本研究数据来源于前瞻性多中心PharmaCool研究。本研究纳入接受治疗性低温治疗，且使用了咪达唑仑和/或苯巴比妥的新生儿。于出生后第2~5天采集血样，测定苯巴比妥、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；以无需追加使用其他抗癫痫药物作为临床疗效的判定标准。<b><i>研究结果：</i></b> 本研究共纳入113例使用苯巴比妥的患儿、118例使用咪达唑仑的患儿，其中68例接受了两种药物联合治疗。仅1-羟基咪达唑仑的清除率受治疗性低温影响。苯巴比妥联合给药可使咪达唑仑清除率升高2.3倍（95%置信区间：1.9~2.9，<i>p</i> < 0.05）。苯巴比妥单药的抗惊厥有效率为65.5%，追加使用咪达唑仑的有效率为37.1%。<b><i>研究结论：</i></b> 对于缺氧缺血性脑病的足月儿及近足月儿，治疗性低温不会影响苯巴比妥或咪达唑仑的清除率。建议采用30 mg/kg的苯巴比妥剂量以达到治疗浓度。苯巴比妥联合给药可显著升高咪达唑仑的清除率。若将苯巴比妥替换为非CYP3A诱导剂作为一线抗惊厥药物，则咪达唑仑的维持剂量需降低50%，以避免出生后最初几日出现药物暴露过量。