Pharmacokinetics of melatonin in preterm infants

Authors

  • Nazakat M. Merchant,

    1. Centre for the Developing Brain, King's College London, London, UK
    2. Centre for the Developing Brain, Imperial College, London, UK
    3. Division of Neonatology, Imperial College Healthcare NHS Trust, London, UK
    4. Division of Neonatology, Guy's and St Thomas' NHS Trust, London, UK
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  • Denis V. Azzopardi,

    1. Centre for the Developing Brain, King's College London, London, UK
    2. Centre for the Developing Brain, Imperial College, London, UK
    3. Division of Neonatology, Imperial College Healthcare NHS Trust, London, UK
    4. Division of Neonatology, Guy's and St Thomas' NHS Trust, London, UK
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  • Ahmed F. Hawwa,

    1. Clinical and Practice Research Group, School of Pharmacy, Medical Biology Centre, Queen's University, Belfast, UK
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  • James C. McElnay,

    1. Clinical and Practice Research Group, School of Pharmacy, Medical Biology Centre, Queen's University, Belfast, UK
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  • Benita Middleton,

    1. Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
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  • J. Arendt,

    1. Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
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  • Tomoki Arichi,

    1. Centre for the Developing Brain, King's College London, London, UK
    2. Centre for the Developing Brain, Imperial College, London, UK
    3. Division of Neonatology, Imperial College Healthcare NHS Trust, London, UK
    4. Division of Neonatology, Guy's and St Thomas' NHS Trust, London, UK
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  • Pierre Gressens,

    1. Division of Neonatology, Imperial College Healthcare NHS Trust, London, UK
    2. Inserm, U676, Paris, France
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  • A. David Edwards

    Corresponding author
    1. Centre for the Developing Brain, King's College London, London, UK
    2. Centre for the Developing Brain, Imperial College, London, UK
    3. Division of Neonatology, Imperial College Healthcare NHS Trust, London, UK
    4. Division of Neonatology, Guy's and St Thomas' NHS Trust, London, UK
    • Correspondence

      Professor David Edwards, Centre for the Developing Brain, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.

      Tel.: +020 7188 8364

      Fax: +020 7188 9154

      E-mail: ad.edwards@kcl.ac.uk

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Abstract

Aims

Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials.

Methods

Melatonin was administered to 18 preterm infants in doses ranging from 0.04–0.6 μg kg−1 over 0.5–6 h. Pharmacokinetic profiles were analyzed individually and by population methods.

Results

Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 μg kg−1 h−1 for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml−1. On population pharmacokinetics, clearance was 0.045 l h−1, volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates.

Conclusions

A 2 h infusion of 0.1 μg kg−1 h−1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants.

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