Pharmacokinetics of ibuprofen in very preterm infants with patent ductus arteriosus
A.G.J. Engbers (1), R.B. Flint (2,3,4), S. Völler (1), J. de Klerk (2), I. Reiss (2), P. Andriessen (5), K.D. Liem (6), P.L.J. Degraeuwe (7), S. Croubels (8), J. Millecam (8), K.M. Allegaert (2), C.A.J. Knibbe (1,9), S.H.P. Simons (2)
(1) Department of Systems Biomedicine & Pharmacology, LACDR, Leiden University, Leiden, the Netherlands, (2) Department of Paediatrics, Division of Neonatology, Erasmus MC - Sophia Children’s Hospital, Rotterdam, the Netherlands, (3) Department of Pharmacy, Radboud University Medical Centre, Nijmegen, the Netherlands, (4) Department of Pharmacy, Erasmus MC, Rotterdam, The Netherlands, (5) Department of Neonatology, Máxima Medical Centre, Veldhoven, the Netherlands, (6) Department of Neonatology, Radboud University Medical Centre , Nijmegen, the Netherlands, (7) Department of Paediatrics, Division of Neonatology, Maastricht University Medical Centre, the Netherlands, (8) Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Belgium, (9) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Introduction: The ductus arteriosus is a physiological shunt between the aortic arch and the pulmonary artery that closes spontaneously within hours after birth in term neonates. In preterm infants the ductus is often found to remain open, the so called patent ductus arteriosus (PDA) [1]. Because PDA with a significant left-to-right shunt is associated with increased morbidity and mortality, treatment of a hemodynamically significant PDA is commonly advised and achieved pharmacologically using ibuprofen [2]. However, discussion is still ongoing concerning the optimal dosage, duration and route of administration. An intravenous 3 day-course with 10 mg/kg on day 1 followed by 5 mg/kg on day 2 and 3 is currently suggested by the label, but regimens with either higher daily doses, continuous administration, and oral administration are suggested to be more effective [3]–[5]. To date there is limited information on target concentration or exposure that needs to be achieved, or specific pharmacokinetic information that may guide the use of ibuprofen across this population.
Objectives: The objective of this study was to develop a population PK model for ibuprofen in preterm infants for the treatment of PDA.
Methods: In a prospective cohort study designed to examine the PK and PD of off-label used drugs in preterm infants, neonates born with a gestational age between 24 and 32 weeks in four Dutch neonatal intensive care units were considered for inclusion. Eighty neonates receiving ibuprofen treatment for PDA closure were evaluated. For 69 of these patients detailed information regarding intravenous ibuprofen dosing and patient characteristics were available at the time of data analysis, providing 214 plasma samples in which either R-ibuprofen, S-ibuprofen or both could be quantified using a validated UPLC-UV (ultra-performance liquid chromatography-ultraviolet) analysis method. The median gestational age (GA) of this study population was 26.1 (range 24.0 – 30.1) weeks, and median postnatal age (PNA) was 6 (range 1 - 32) days. The median cumulative dose of ibuprofen was 25 (range 7 to 98) mg/kg and the duration of therapy was median 2 days (range 1 to 14 days).
The total concentration of ibuprofen (sum of R- and S-ibuprofen) plasma concentrations was modelled using NONMEM V7.3.0 [6]. GA, PNA, postmenstrual age, gender, birthweight and actual bodyweight (WT) were tested as covariates. Covariates were included based on a forward inclusion and backward exclusion principle (p<0.05 and p<0.01 respectively), and were only included if their effect was biologically plausible. The final model was validated using normalized prediction distribution errors and by performing a bootstrap.
Results: In a one-compartment model, population mean clearance (CL) was estimated 0.011 L/h with an interindividual variability (IIV) of 63.0%, (RSE 8.1%), and the mean central volume of distribution (Vd) 0.322 L (13.7% IIV, RSE 5.7%). IIV in CL was best predicted by the covariates PNA and GA (p<0.0001 and p<0.001 respectively). CL linearly increased by 23.2% per week of gestation. For PNA a power function with an estimated exponent of 1.83 (RSE 11.5%) led to the best fit. WT was found to influence Vd, which was best described by a power model with an exponent of 0.474 (RSE 34.2%). All parameter estimates were within the 95% confidence intervals as calculated by the bootstrap.
Conclusions: Ibuprofen CL in preterm infants is affected by both GA and PNA. This underlines the need for age specific ibuprofen dosing guidelines. The results of this analysis can be used as a basis for exploring the stereopharmacokinetics of the R- and S-enantiomers of ibuprofen, ultimately to guide individualised treatment of preterm infants with ibuprofen.
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