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.