A.G.J. Engbers (1), R.B. Flint (2,3,4), S. Völler (1,5), J.C.A de Klerk (2), I.K.M Reiss (2), P. Andriessen (6), K.D. Liem (7), P.L.J. Degraeuwe (8), S. Croubels (9), J. Millecam (9), K.M. Allegaert (2,10), C.A.J. Knibbe (1,11), S.H.P. Simons (2)
(1) Division 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) Division of BioTherapeutics, LACDR, Leiden University, Leiden, the Netherlands, (6) Department of Neonatology, Máxima Medical Centre, Veldhoven, the Netherlands, (7) Department of Neonatology, Radboud University Medical Centre , Nijmegen, the Netherlands, (8) Department of Paediatrics, Division of Neonatology, Maastricht University Medical Centre, the Netherlands, (9) Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Belgium, (10) Department of Development and Regeneration, KU Leuven, Belgium (11) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Racemic ibuprofen is widely used in neonatal intensive care units for the treatment of preterm neonates with patent ductus arteriosus (PDA). While postnatal age has been identified as driving factor of the pharmacokinetics of ibuprofen, a bodyweight-based dosing regimen of 10-5-5 mg/kg administered on three consecutive days is still widely used.[1] Only a limited number of studies considered the pharmacokinetics of the separate enantiomers of ibuprofen, while only the S-ibuprofen enantiomer is pharmacologically active.[2,3] This study therefore develops a population pharmacokinetic model of both enantiomers of ibuprofen in preterm neonates, needed to develop optimized dosing guidelines.
Methods: Data from the DINO study (Drug dosage Improvement NeOnates, NCT 02421068) were available for analysis. This study included preterm infants requiring one of nine frequently used off-label drugs in this population. Pharmacokinetic and pharmacodynamic data were collected opportunistically. A total of 210 samples were available from 67 preterm infants in which S-ibuprofen could be quantified above the limit of quantification (LOQ) of 1 µg/mL. In 65 of the 210 samples R-ibuprofen concentrations were above the LOQ. Covariates that were available for analysis were postnatal age (median at treatment initiation 3 (range 1-12) days), gestational age (26 (24-30) weeks), postmenstrual age (27.0 (24.6-31.6) weeks), birthweight (0.87 (0.47-1.5) kg), current weight (0.82 (0.45-1.6) kg), small for gestational age (defined as birth weight < 10th percentile for their gestational age, n=7) and gender. Neonates were treated according to the standard of care in different hospitals, resulting in a varied dosing regimen. The regimen started with a median loading dose of 10.2 (range 5.0-22.4) mg/kg, followed by a maintenance dose of 7.0 (4.4-28.4) mg/kg for two days. This cycle was repeated until closure of the ductus was achieved.
A population pharmacokinetic model was developed in NONMEM (V.7.3).[4] The total dose of ibuprofen was assumed to consist of 50% S- and 50% R-ibuprofen, and was therefore divided by two and directed to two compartments. First a pharmacokinetic model of S-ibuprofen was developed, because of the limited number of available R-ibuprofen concentrations. For this model covariates were evaluated using stepwise covariate modelling, using significance levels of p ≤ 0.01 for forward inclusion and p ≤ 0.005 for backwards elimination. R-ibuprofen concentrations were then added to the model to describe the pharmacokinetics of both enantiomers in parallel. The M3-method was used to describe the data below the limit of quantification.[5] In the enantiomer model potential conversion of R-ibuprofen to S-ibuprofen was examined, as well as the effect of postnatal age on the elimination of R-ibuprofen, based on the results of Gregoire et al.[3]
Results: For a typical preterm neonate (born after 26 weeks, appropriate for gestational age and 3 days old) clearance of S-ibuprofen (CLS) and volume of distribution (VS) were 3.9 mL/h (RSE 12%) and 236 mL (RSE 7%), with inter-individual variability of 44.9% (RSE 16%) and 22.7% (RSE 33%) respectively. Maturation of CLS was substantially affected by postnatal age with an estimated exponent of 2.33 (RSE 16%), resulting in a 127% increase in CLS in one week for an infant starting treatment at a postnatal age of 1 day. Additionally, CLS was found to increase with gestational age (exponent of 5.47, RSE 19%) and CLS was estimated to be 3.9 times higher compared to small for gestational age infants (RSE 34%). Estimated clearance of R-ibuprofen (CLR) was 153 mL/h (RSE 18%) which increased linearly with postnatal age with a slope of 19.4 mL/h/day (RSE 49%). Volume of distribution of R-ibuprofen (VR) was estimated at 344 mL (RSE 13%). Both VS and VR increased with current body weight, One exponent of 0.456 (RSE 36%) was able to describe this change for both parameters and performed similarly to when two parameters were estimated. Conversion from R- to S-ibuprofen could not be identified.
Conclusions: The findings of this study suggest that the current practice of bodyweight-based dosing of ibuprofen in preterm neonates may be suboptimal and that dosing based on PNA may lead to a more uniform area under the concentration-time curve. When target exposure has been defined, model-based simulations can form the basis for the development of individualized dosing regimen.
References:
[1] Hirt, D. et al. Br. J. Clin. Pharmacol. 65: 629–636, 2008.
[2] Gregoire, N. et al. J. Clin. Pharmacol. 44: 1114–24, 2004.
[3] Gregoire, N. et al. J. Clin. Pharmacol. 48: 1460–8, 2008.
[4] Beal, S. L. et al. NONMEM 7.3.0 Users Guides. ICON Development Solutions, Ellicott City, Maryland, USA.
[5] Beal S.L. J. Pharmacokinet. Pharmacodyn. 28: 481–504, 2001.
Reference: PAGE 28 (2019) Abstr 9112 [www.page-meeting.org/?abstract=9112]
Poster: Drug/Disease Modelling - Paediatrics