A preliminary study on pharmacokinetics of oral indomethacin in premature infants in north India.

BACKGROUND & OBJECTIVES Patent ductus arteriosus (PDA) is a frequent complication in premature infants. Intravenous indomethacin is the standard mode of medical therapy and has been shown to be efficacious in closing the ductus. In our setup, oral indomethacin is being regularly used for medical treatment of suspected or clinically diagnosed PDA. Non-availability of the parenteral preparation and lack of information regarding the pharmacokinetic disposition of indomethacin in the premature infants in north Indian population led us to conduct this pharmacokinetic study with oral indomethacin. METHODS Twenty premature infants with gestational age 30.3 +/- 0.3 wk and birth weight, 1209.8 +/- 39.5 g; admitted to the neonatal unit of the Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh were enrolled in the study. Indomethacin was administered in a single oral dose of 0.2 mg/kg and blood samples were collected through an indwelling vascular catheter at 0 and 1, 2, 4, 8 and 12 h after administration of indomethacin. Plasma indomethacin concentrations were assayed by spectrofluorometric technique. RESULTS Large interindividual variability was observed for peak plasma concentrations (Cmax; 137.9 +/- 14.0 ng/ml), elimination half-life (t1/2 el; 21.4 +/- 1.7 h) and area under the plasma concentrations time curve (AUC0-infinity;4172 +/- 303 ng.h/ml) in these infants. Variables like birth weight, and sex did not have any sigiificant effect on indomethacin pharmacokinetics. However, the plasma t1/2 el of indomethacin was significantly (P < 0.01) larger in older infants (gestational age > 30 wk) in comparison to younger ones (gestational age < or = 30 wk). There was a negative correlation between gestational age and elimination t1/2 (r = -0.77). INTERPRETATION & CONCLUSION In conclusion, indomethacin pharmacokinetics showed a wide variability in premature infants. In view of these findings it can be suggested that infants of smaller gestational age are at greater risk of cumulative toxicity if more than one dose of indomethacin is given. With advancing age, metabolism as well as elimination of drug is faster that may require modification in indomethacin dose to achieve therapeutic response. These preliminary results may be of use in designing future pharmacokinetic studies of oral indomethacin in preterm neonates on a larger sample.