Pharmacokinetics of intravenously administered indomethacin in premature infants

We studied the pharmacokinetics of indomethacin (0.3 mg/kg) given intravenously in 17 premature infants to promote closure of persistent ductus arteriosus. The decay of indomethacin generally showed an initial rapid distribution (alpha) phase followed by a slower elimination (beta) phase. The mean half-life of elimination (20.7 +/- 8 hours) was three times longer, and the mean clearance rate (13 +/0 9.5 ml/kg/hour) was seven times less than that reported in adults. The indomethacin clearance rate was linearly correlated with postnatal age (r = 0.71, P < 0.01). There was strong evidence of later re-entry of indomethacin into the plasma, suggesting that enterohepatic recirculation may be common in premature infants and may contribute to the relatively long half-life of elimination. Our data do not clarify the question of target concentration or minimal exposure time above which permanent closure may occur, but the group of infants who had permanent PDA closure after only one dose (8/17) had a significantly higher plasma indomethacin concentration time integral than the group (9/17) who needed more than one dose (P < 0.01). A 24-hour dosage interval was often sufficient when an iv indomethacin bolus of 0.3 mg/kg was used but, below the age of nonresponsiveness to indomethacin, a shorter interval may be preferable as postnatal age increases.