Article date: May 2008
By: Déborah Hirt, Bart Van Overmeire, Jean‐Marc Treluyer, Jean‐Paul Langhendries, Arnaud Marguglio, Mark J. Eisinger, Paul Schepens, Saïk Urien, in Volume 65, Issue 5, pages 629-636
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
AIMS
To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.
METHODS
Sixty‐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.
RESULTS
Ibuprofen 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.
CONCLUSIONS
To 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.
DOI: 10.1111/j.1365-2125.2008.03118.x
View this article