Pharmacologic, Pharmacodynamic, and Pharmacokinetic Considerations with Intravenous Ibuprofen Lysine

Patent ductus arteriosus (PDA) is a common complication in preterm infants. An intravenous (IV) cyclooxygenase (COX) inhibitor is the pharmacotherapy of choice. Concerns over adverse effects associated with the traditional treatment, IV indomethacin, have led to the investigation of other COX inhibitors to assist closure of PDA. IV ibuprofen lysine is a COX inhibitor that demonstrates similar efficacy to indomethacin with few adverse effects. In addition, IV ibuprofen lysine does not cause reductions in cerebral, renal, and mesenteric blood flow that can be seen with indomethacin, and thus ibuprofen therapy is not associated with reduced renal function. Ibuprofen is primarily metabolized by cytochrome P450 (CYP) 2C9. The immaturity of neonatal biotransformation pathways has a pronounced effect on the pharmacokinetic parameters of ibuprofen, particularly because CYP2C9 enzyme activity is known to be very low at birth and to increase rapidly over the first several days of life. Ibuprofen is highly bound to albumin, raising concern that ibuprofen may displace bilirubin and subsequently increase free bilirubin concentrations. However, the ibuprofen concentrations achieved with approved dosing with IV ibuprofen lysine are lower than those expected to result in displacement of bilirubin and related adverse effects. Factors such as gestational age and CYP2C9 polymorphism may affect ibuprofen metabolism and therefore optimal dosing, but further clinical investigation is needed in these areas. Other areas for future investigation include prolonged dosing regimens, prophylactic administration, and alternate indications. At the approved dose, IV ibuprofen lysine is a safe, effective pharmacologic agent to promote closure of PDAs in preterm infants.