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Rapidly maturing fentanyl clearance in preterm neonates
  1. Swantje Völler1,
  2. Robert B Flint2,3,4,
  3. Peter Andriessen5,
  4. Karel Allegaert6,
  5. Luc J I Zimmermann7,
  6. Kian D Liem8,
  7. Birgit C P Koch4,
  8. Sinno H P Simons2,
  9. Catherijne A J Knibbe1,9
  10. DINO study group
    1. 1 Division of Pharmacology, Division Systems Pharmacology and Biomedicine, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
    2. 2 Division of Neonatology, Department of Pediatrics, Erasmus MC–Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
    3. 3 Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
    4. 4 Department of Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
    5. 5 Division of Neonatology, Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands
    6. 6 Division of Neonatology, Department of Pediatrics, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands
    7. 7 Department of Pediatrics, School of Oncology and Developmental Biology, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands
    8. 8 Division of Neonatology, Department of Pediatrics, Radboudumc, Nijmegen, The Netherlands
    9. 9 Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands
    1. Correspondence to Dr. Swantje Völler, Division of Pharmacology, Division Systems Pharmacology and Biomedicine, Leiden Academic Centre for Drug Research, Leiden University, Leiden 2300 RA, The Netherlands; s.voller{at}lacdr.leidenuniv.nl

    Abstract

    Background Fentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation.

    Methods 442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9–31.9) weeks, postnatal age: 3 (range 0–68) days, bodyweight 1.00 (range 0.39–2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations.

    Results Fentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (µg/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0–4 days and 5–9 days in comparison to 10 days and older.

    Conclusion Because of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing.

    • pharmacology
    • neonatology
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    Footnotes

    • SV and RBF contributed equally.

    • Contributors SV, RBF: conception and design, analysis, interpretation of data, drafting and revising the manuscript, final approval. PA, LJIZ, KDL: acquisition of data, interpretation of data, revising the manuscript, final approval. KA: interpretation of data, drafting and revising the manuscript, final approval. BCPK: analysis of data, interpretation of data, revising the manuscript, final approval. SHPS, CAJK: conception and design, analysis, interpretation of data, revising the manuscript, final approval.

    • Funding The DINO study and all accompanying research were funded by the Netherlands Organisation for Health Research and Development ZonMw (grant number: 836011022).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Dick Tibboel, Monique van Dijk, Ronald de Groot, David Burger, Irwin Reiss, Koos Burggraaf.

    • Patient consent for publication Not required.

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