Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model

Swantje Voller*, Robert B. Flint, Fouzi Beggah, Irwin Reiss, Peter Andriessen, Luc J. Zimmermann, John N. van den Anker, Kian D. Liem, Birgit C. P. Koch, Saskia de Wildt, Catherijne A. J. Knibbe, Sinno H. P. Simons

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Although midazolam is a frequently used sedative in neonatal intensive care units, its use in preterm neonates has been off-label. Recently, a new dosing advice for midazolam for sedation on intensive care units has been included in the label (0.03 mg/[kg center dot h] for preterm neonates 32 weeks). Concentration-time data of a prospective multicenter study (29 patients, median gestational age 26.7 [range 24.0-31.1 weeks]) were combined with previously published data (26 patients, median gestational age 28.1 [range 26.3-33.6 weeks]), and a population pharmacokinetic model describing the maturation of midazolam pharmacokinetics was developed in NONMEM 7.3. Clearance was 73.7 mL/h for a neonate weighing 1.1 kg and changed nonlinearly with body weight (exponent 1.69). Volume of distribution increased linearly with body weight and was 1.03 L for a neonate weighing 1.1 kg. Simulations of the newly registered dosing show considerable differences in steady-state concentrations in preterm neonates. To reach similar steady-state concentrations of 400 mu g/mL (+/- 100 mu g/mL), a dose of 0.03 mg/(kg center dot h) is adequate for neonates >= 1 kg and 2 kg and

Original languageEnglish
Pages (from-to)1300-1308
Number of pages9
JournalJournal of Clinical Pharmacology
Issue number10
Publication statusPublished - Oct 2019


  • drug metabolism
  • fetal medicine
  • neonatology
  • pharmacokinetics
  • pharmacometrics
  • population pharmacokinetics

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