title: Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults.
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.
authors.affiliation: Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands; Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Intensive Care, Rotterdam, The Netherlands.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Caroline D
authors.initials: CD
authors.lastname: van der Marel
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics*; D000328:Adult; D000375:Aging / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D008954:Models, Biological; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
keywords: allometry; clearance; paracetamol; pediatric; pharmacokinetics