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

  • Laurent M.A. Favié (Contributor)
  • Floris Groenendaal (Contributor)
  • Toine C. G. Egberts (Contributor)
  • Arno van Heijst (Contributor)
  • Monique Rijken (Contributor)
  • Johanna H. van der Lee (Contributor)
  • Marcel P. H. van den Broek (Contributor)
  • Koen P. Dijkman (Contributor)
  • Carin M. A. Rademaker (Contributor)
  • Sinno H. P. Simons (Contributor)
  • Timo R. de Haan (Contributor)
  • Filip Cools (Contributor)
  • Debbie H G M Nuytemans (Contributor)
  • Peter Dijk (Contributor)
  • Henrica L. M. Van Straaten (Contributor)
  • Alexandra Zecic (Contributor)
  • Inge A. Zonnenberg (Contributor)
  • Alwin D. R. Huitema (Contributor)
  • Frank van Bel (Contributor)



    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.
    Date made available1-Aug-2019
    PublisherUniversity of Groningen

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