LAUSR

Interindividual variability in the development (rate and extent) of drug clearance pathways(1) may contribute to the observed 14-fold variability in indomethacin (IND) systemic exposure(2), and thus, the drug’s unpredictable efficacy and toxicity profile following standard dosing regimens. Indomethacin is prescribed commonly in the Neonatal Intensive Care Unit for prophylaxis from Intraventricular Hemorrhage (IVH) and medical closure of Patent Ductus Arteriosus (PDA). Up to 25% of preterm infants fail medical closure with indomethacin and other NSAIDs and go on to require surgical PDA ligation. Thus, improved understanding of indomethacin dosing in individual infants could improve medical care. Indomethacin is primarily metabolized to inactive moieties by direct acylglucuronidation by UGT2B7 and UGT1A9(3)and cytochrome P450 2C9 (CYP2C9)mediated O-demethylation(4). In the context of a rapidly maturing preterm infant, assessment of the relative contribution of the competing glucuronidation and CYP pathways via urine collection over the first 24-48 hours following drug administration, a common practice in neonatal research (5, 6), may not reflect the relative metabolic contributions later in the treatment course when the patients are older (and more mature).