Chenguang Wang (1,2), Karel Allegaert (3), Dick Tibboel (3), Meindert Danhof (1), Caroline D. van der Marel (4), Ron A.A. Mathot (5), Catherijne A.J. Knibbe (1,6)
(1) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands (2) Erasmus MC Sophia Children’s Hospital, Intensive Care and Department of Paediatric Intensive Care, Rotterdam, The Netherlands (3) Department of Development and Regeneration, KU Leuven and Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium (4) Department of Anesthesiology, Erasmus MC, Rotterdam, The Netherlands (5) Departments of Hospital Pharmacy and Clinical Pharmacology, Academic Medical Centre, Amsterdam, The Netherlands (6) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: In order to characterize the variation in pharmacokinetics of paracetamol across the human age span, we performed a population pharmacokinetic analysis from preterm neonates to adults with specific focus on clearance.
Methods: Concentration-time data obtained in 220 neonates (post-natal age 1-76 days, gestational age 27-42 weeks) [1,2,3], infants (0.11-1.33 years) [4,5], children (2-7 years) [6] and adults (19-34 years) [7,8] were analysed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight-dependent exponent [9] were tested.
Results: Between preterm neonates and adults, linear bodyweight functions were identified for Q2, Q3, V1, V2, and V3, while for CL a power function with a bodyweight-dependent exponent k was identified (CLi=(BWi/70)k ).The exponent k was found to decrease in a sigmoidal manner with bodyweight from 1.2 to 0.75, with half the decrease in exponent reached at 12.2kg. No other covariates such as age were identified.
Conclusions: A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the entire human lifespan (preterm and term neonates, infants, children, and adults) was developed in which CL was found to change in a non-linear manner with bodyweight. The results may provide insight in the exact relation between weight and CL and as such provide a guide for individualized dosing in children. Once the therapeutic target concentration is known, corresponding appropriate doses can be easily calculated based on this model.
This abstract is adapted from the publication by Wang et al,. The Journal of Clinical Pharmacology 2013 Dec 30. doi:10.1002/jcph.259
References:
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[2] Allegaert K, Van der Marel CD, Debeer A, et al. Pharmacokinetics of single dose intravenenous propacetamol in neonates: effect of gestational age. Arch Dis Child Fetal Neonatal Ed. 2004;89(1):F25-F28.
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[6]van der Marel CD. Paracetamol, Widely used Hardly understood. Rotterdam: Erasmus University Medical Center; 2003.
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[8]Gregoire N, Hovsepian L, Gualano V, Evene E, Dufour G, Gendron A. Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose. Clin Pharmacol Ther. 2007; 81(3):401–405.
[9]Wang C, Peeters MY, Allegaert K, et al. A bodyweight-dependent allometric exponent for scaling clearance across the human life-span. Pharm Res. 2012; 29(6):1570–1581.
Reference: PAGE 23 () Abstr 3108 [www.page-meeting.org/?abstract=3108]
Poster: Drug/Disease modeling - Paediatrics