Calvier EAM (1), Krekels EHJ (1), Välitalo PAJ (1), Rostami-Hodjegan A (2), Tibboel D (3), Danhof M (1), Knibbe CAJ (1,4)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands, (2) Manchester Pharmacy School, University of Manchester, Manchester, UK, (3) Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands, (4) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS) [1] 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 drugs cleared through hepatic metabolism or glomerular filtration (GF).
Methods: A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12620 hypothetical drugs. In one scenario, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration rate were included in simulations of ‘true’ paediatric CLp [2]. In a second scenario, also maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration [2], and haematocrit [3] were included in these simulated ‘true’ paediatric CLp values. For the first scenario, an allometric exponent was estimated based on ‘true’ CLp, while for both scenarios, the prediction error (PE) of AS-based paediatric CLp predictions was assessed.
Results: In the first scenario, the estimated allometric exponent ranged from 0.50 to 1.20 depending on age and drug properties, with PE of AS-based paediatric CLp predictions reaching up to 253% in neonates. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS resulting in accurate CLp predictions above five years of age.
Conclusions: Using PBPK principles, it was shown that there is no evidence for one unique allometric exponent in paediatrics, even in scenarios that only consider size-related changes. As PE is most sensitive to the exponent, drug properties and maturation in younger children, AS leads to increasingly worse predictions with decreasing age.
References:
[1] Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin. Pharmacokinet. (1997) 33(5):313–27
[2] Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin. Pharmacokinet. (2006) 45(9):931–56
[3] Irwin JJ, Kirchner JT. Anemia in children. Am. Fam. Physician. (2001) 64(8):1379–86
Reference: PAGE 25 (2016) Abstr 5729 [www.page-meeting.org/?abstract=5729]
Poster: Drug/Disease modeling - Paediatrics