Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults

Chenguang Wang, Karel Allegaert, Dick Tibboel, Meindert Danhof, Caroline D. van der Marel, Ron A. A. Mathot, Catherijne A. J. Knibbe

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33 Citations (Scopus)

Abstract

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. Concentration-time data obtained in 220 neonates (post-natal age 1-76 days, gestational age 27-42 weeks), infants (0.11-1.33 yrs), children (2-7 yrs) and adults (19-34 yrs) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight-dependent exponent were tested. 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  = CLp  × (BW/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 12.2 kg. No other covariates such as age were identified. A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the pediatric age-range was developed. Clearance was found to change in a nonlinear manner with bodyweight. Based on the final model, dosing guidelines are proposed from preterm neonates to adolescents resulting in similar exposure across all age ranges
Original languageEnglish
Pages (from-to)619-629
JournalJournal of clinical pharmacology
Volume54
Issue number6
DOIs
Publication statusPublished - 2014

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