Emily Ratcliffe 1, Elke H.J Krekels 2,3, An Vermeulen 4, Catherijne A.J Knibbe 3,5, Amy Cheung 1,2, Michael Chappell 1
1 School of Engineering, University of Warwick (, ), 2 Certara Inc (, USA), 3 Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University (, ), 4 Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University (, ), 5 Department of Clinical Pharmacy, St. Antonius Hospital (Utrecht, The Netherlands)
Background: In the absence of paediatric data, accurate scaling of drug clearance is crucial for determining safe and effective doses. While Population Pharmacokinetic (PopPK) and Physiologically-Based Pharmacokinetic (PBPK) modelling are the gold standards for predictions, PBPK models are often resource-intensive and limited by data availability. As a result, simpler, empirical methods are desirable. These approaches range from basic allometric techniques, such as linear bodyweight-based scaling or fixed allometric scaling with an exponent of 0.75 (AS0.75), to more advanced models that integrate AS0.75 with maturation functions within a PopPK framework. The absence of standardised selection criteria often leads to inconsistent application of clearance scaling approaches. Developing a framework for selecting appropriate methods is vital to streamline the regulatory approval process and safeguard patient safety. To aid in selecting accurate methods, decision tables have been proposed that consider paediatric age and drug properties [2]. This research is conducted within Work Package 5 of the EU project ERAMET [3], which aims to accelerate the adoption of modelling and simulation (M&S) and to establish a credibility framework for orphan and paediatric drug development.
Project Aim: The primary aim of this study was to evaluate, based on published adult and paediatric drug clearance values, whether these decision tables provide appropriate guidance for selecting suitable paediatric clearance scaling methods.
Methods: A comprehensive literature search (from January 2000 onwards) was conducted to identify paediatric plasma clearance (CL) values for a set of renally cleared drugs. Strict exclusion criteria were applied, excluding adults, preterm neonates, and subjects with organ failure or severe clinical cofounders to ensure data reflected physiological maturation rather than pathological variation. Reported median or mean bodyweights were extracted from the publications; where unavailable, median values for defined age groups were derived from World Health Organisation (WHO) growth charts [4] to generate standardised observed CL values from extracted covariate models. Adult CL values and physiochemical properties (fraction unbound, primary elimination pathway and main plasma binding protein) were sourced to select the recommended scaling method from the established decision tables [2]. Adult CL was scaled using the reported median/mean bodyweight from the source publication, or a standard 70 kg bodyweight where specific data were lacking, to produce predicted paediatric values. Predictive performance was assessed by calculating the Percentage Error (PE) between scaled and observed values, using a predefined acceptance range of ±50% based on the methodology established on previous decision table validation [2].
Results: Data were evaluated for three drugs primarily cleared through glomerular filtration only (i.e., gentamicin, vancomycin, and teicoplanin), as well as three drugs cleared through both glomerular filtration and active tubular secretion (i.e., meropenem, cefuroxime, and piperacillin). The generated decision tables demonstrated high predictive accuracy in selecting scaling methods. Across 85 analysed data points, 96.5% of the scaled predictions remained within the predefined acceptance range of ±50% prediction error. Only 3 out of 85 data points fell outside this threshold. These deviations occurred in the 2-year and 5-year age groups, and the magnitude of error for these outliers was marginal, with a maximum deviation of 52.9%.
Conclusion: These findings indicate that the evaluated decision tables provide a highly reliable, evidence-based framework for selecting accurate paediatric clearancescaling methods for renally cleared drugs. The minor deviations observed are likely due to inherent data variability or differing PopPK modelling techniques in the source literature, rather than flaws in the decision table logic. Ongoing work will expand this regulatory qualification framework to include hepatically cleared drugs.
References:
[1] Zhou W, Johnson TN, Xu H, et al. Predictive performance of physiologically based pharmacokinetic and population pharmacokinetic modeling of renally cleared drugs in children. CPT Pharmacometrics Syst Pharmacol. 2016;5(9):475-483. doi:10.1002/psp4.12101
[2] van Rongen A, Krekels EH, Calvier EA, de Wildt SN, Vermeulen A, Knibbe CA. An update on the use of allometric and other scaling methods to scale drug clearance in children: towards decision tables. Expert Opin Drug Metab Toxicol. 2022;18(2):99-113. doi:10.1080/17425255.2021.2027907
[3] ERAMET Consortium. Ecosystem for Rapid Adoption of Modelling and Simulation Methods to Address Regulatory Needs in the Development of Orphan and Paediatric Medicines. Horizon Europe Project 101137141; 2024.
[4] World Health Organization. WHO Child Growth Standards: Methods and development: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Geneva: World Health Organization; 2006.
Reference: PAGE 34 (2026) Abstr 11876 [www.page-meeting.org/?abstract=11876]
Poster: Drug/Disease Modelling - Paediatrics