title: Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?
abstract: Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of 'true' paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated 'true' paediatric CLpvalues. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLppredictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on 'true' CLp. In the first scenario, the PE of AS0.75-based paediatric CLppredictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLppredictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age.
authors: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Gorlaeus Laboratories, Einsteinweg, 552333 CC, Leiden, The Netherlands.
authors: Elisa A M
authors: EA
authors: Calvier
authors: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Gorlaeus Laboratories, Einsteinweg, 552333 CC, Leiden, The Netherlands.
authors: Elke H J
authors: EH
authors: Krekels
authors: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Gorlaeus Laboratories, Einsteinweg, 552333 CC, Leiden, The Netherlands.
authors: Pyry A J
authors: PA
authors: Välitalo
authors: Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors: Amin
authors: A
authors: Rostami-Hodjegan
authors: Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Dick
authors: D
authors: Tibboel
authors: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Gorlaeus Laboratories, Einsteinweg, 552333 CC, Leiden, The Netherlands.
authors: Meindert
authors: M
authors: Danhof
authors: Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Gorlaeus Laboratories, Einsteinweg, 552333 CC, Leiden, The Netherlands. c.knibbe@antoniusziekenhuis.nl.|Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. c.knibbe@antoniusziekenhuis.nl.
authors: Catherijne A J
authors: CA
authors: Knibbe
mesh_terms: D000293:Adolescent; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood*
chemical_list: D004364:Pharmaceutical Preparations