Clinical Pharmacology of Ibuprofen and Indomethacin in Preterm Infants with Patent Ductus Arteriosus

Background: Ibuprofen and indomethacin are potent non-selective cyclo-oxygenase inhibitors and inhibit prostaglandin E2 synthesis. The patent ductus arteriosus (PDA) occurs in more than 70% of preterm infants weighing <1500 g. Prostaglandin E2 relaxes smooth muscle, tends to inhibit the closure of PDA, yields vasodilatation of the afferent renal arterioles and maintains glomerular filtration rate (GFR). Ibuprofen and indomethacin inhibiting prostaglandin E2 synthesis close PDA and reduce GFR with consequent decrease of urine output and increase of serum creatinine concentrations. Aims: The aims of this study are to give the definitive estimates of PDA closure rate following ibuprofen or indomethacin treatment and to evaluate the extent of renal side effects following the administration of these drugs to preterm infants. Other aims are to review the metabolism and the pharmacokinetics of ibuprofen and indomethacin in preterm infants with PDA. Methods: The bibliographic search was performed using PubMed and EMBASE databases as search engines, January 2013 was the cutoff point. Results: The %PDA closed by ibuprofen (n=24) and indomethacin (n=24) is 77.7 +/- 14.1 and 77.3 +/- 11.0, respectively. For ibuprofen, the gestational age of the infants included in the study ranged from 25.0 to 39.0 weeks (mean +/- SD=29.3 +/- 3.1 weeks). The %PDA did not correlate with the gestational age (p=0.2516). For indomethacin, the gestational age of infants included in the study ranged from 25.0 and 39.0 weeks (mean +/- SD=29.4 +/- 2.9 weeks). The %PDA did not correlate with the gestational age (p=0.3742). The treatment with ibuprofen reduces the urine output and increases the serum creatinine concentrations less extensively than indomethacin. The half-life (t(1/2)) of ibuprofen and indomethacin is lengthened and the clearance is reduced in preterm infants as compared with fullterm infants. Conclusions. Ibuprofen and indomethacin are equally effective in closing PDA. Treatment with ibuprofen decreases the risk of renal failure. Ibuprofen has the most favourable risk/benefit ratio. The rate of metabolism is reduced and t(1/2) is lengthened in prematures as compared with term infants.