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Title: Pharmacokinetics of melatonin as a neuroprotectant in preterm infants
Author: Merchant, Nazakat
ISNI:       0000 0005 0734 5850
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Background and purpose: Advances in perinatal care have increased survival rates of infants but long-term neurodisability and social consequences have remained unchanged over the last decade. Preterm infants are deprived of the normal intrauterine exposure to maternal melatonin and experimental studies suggest that melatonin has a neuroprotective effect on cerebral white matter injury. However, pharmacokinetic data on melatonin in preterm infants are lacking, which hinders potential therapeutic trials. The aims of this study were to determine the pharmacokinetics of melatonin in the relevant preterm population, assess the tolerability of melatonin and determine a dose regime that would allow replication of adult melatonin levels. Methods: In a multi-centre, single dose escalation/de-escalation, open label study in preterm infants less than 31 weeks gestation, melatonin was administered to eighteen infants in doses ranging from 0.04-0.6 micrograms/kilograms, over 0.5-6 hours. Pharmacokinetic profiles were analysed individually and by population methods. Results: Baseline melatonin was largely undetectable. At the highest and lowest doses half-life could not be calculated due to blood concentrations not reaching a consistent steady state, but infants receiving melatonin at 0.1 micrograms/kilogram/hour for 2 hours showed a median half-life of 15.82 hours and median maximum plasma concentration of 203.3 picograms/millilitre. Population pharmacokinetic analysis showed that clearance was 0.045 litre/hour, volume of distribution 1.098 litres and elimination half-life 16.91 hours with gender (p=0.047) and race (p < 0.0001) as significant covariates. Melatonin infusion appeared to be well tolerated in preterm infants. Conclusions: The pharmacokinetic profile of melatonin in preterm infants differs from that of adults. Slow clearance makes replication of adult and thus fetal concentrations of melatonin problematic. Further studies are needed to confirm these findings.
Supervisor: Counsell, Serena ; Azzopardi, Denis ; Edwards, David Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available