An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates.• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. WHAT THIS STUDY ADDS• A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen.• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMSTo describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety. METHODSSixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg -1 of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure. RESULTSIbuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h -1 (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3) 1.49 . AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l -1 h (or AUC3D < 900 mg l -1 h) and in 91% when AUC1D > 600 mg l -1 h (or AUC3D > 900 mg l -1 h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated. CONCLUSIONSTo achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg -1 for neonates younger than 70 h, 14, 7, 7 mg kg -1 for neonates between 70 and 108 h and 18, 9, 9 mg kg -1 for neonates between 108 and 180 h.

Continuous Infusion of Ibuprofen for Treatment of Patent Ductus Arteriosus in Very Low Birth Weight Infants

“…The reported closure rate using IBU is between 57 and 89% and is inversely related to gestational age [8]. Increased and earlier doses of IBU have recently been recommended in an effort to improve its efficacy [9,10,11], but the tolerability and safety of these regimens need to be assessed in larger populations. Also, the oral route has been tested, but the results need to be confirmed in larger trials, especially in extremely low birth weight infants [12].…”

Displacement of Bilirubin From Albumin by Ibuprofen In Vitro

“…dose of 10 mg/kg (25,26). However, neonates are often treated with several doses with 12-h intervals and may reach even higher plasma concentrations of ibuprofen.…”

Gastrointestinal complications associated with ibuprofen therapy for patent ductus arteriosus

“…However, serum creatinine, fluid intake immediately preceding ibuprofen and urine output both during and after ibuprofen treatment were not different. Although ibuprofen kinetics influences the rate of PDA closure, it is independent of GA. 28 Ibuprofen clearance is dependent on postnatal age and maturation of cytochrome P450 subfamily complex. 28 The earlier initiation of ibuprofen in infants who developed SIP suggests that ibuprofen clearance and regional prostaglandin concentrations may have played a role in the development of SIP.…”

“…Although ibuprofen kinetics influences the rate of PDA closure, it is independent of GA. 28 Ibuprofen clearance is dependent on postnatal age and maturation of cytochrome P450 subfamily complex. 28 The earlier initiation of ibuprofen in infants who developed SIP suggests that ibuprofen clearance and regional prostaglandin concentrations may have played a role in the development of SIP. Novack et al 29 also noted higher blood urea nitrogen in infants with focal bowel perforation associated with indomethacin, but only after initiating treatment with indomethacin.…”