II-60 Anne van Rongen

Decision tables for the selection of allometric and other methods to scale adult drug clearance to children: making it as simple as possible but not simpler

Anne van Rongen*(1), Elke H.J. Krekels*(1), Elisa A.M. Calvier (2), Saskia N. de Wildt (3,4), An M. Vermeulen (5,6), Catherijne A.J. Knibbe (1,7)

(1) Div. of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (2) Sanofi Pharmacokinetics-Dynamics and Metabolism (PKDM), Translational Medicine and Early Development, Sanofi R&D, Montpellier, France, (3) Dept. of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands , (4) Intensive Care and Dept. of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands, (5) Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium, (6) Janssen R&D, A Division of Janssen Pharmaceutica NV, Beerse, Belgium, (7) Dept. of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. * These authors contributed equally

Objectives: When pediatric data for a drug are not available, allometric and other methods are generally applied to scale adult drug clearance across the pediatric age-range. Recently, the systematic accuracy of five commonly used pediatric scaling methods has been established against gold standard PBPK predictions by exploring their performance for up to 84.000 hypothetical drugs with realistic ranges of drug properties [1–6]. We present decision tables derived from these systematic analyses to provide a priori guidance on the selection of pediatric clearance scaling methods for both novel drugs for which no pediatric data are available and existing drugs used unlicensed or off-label in clinical practice [7].

Methods: Results of the original studies on the systematic accuracy of commonly used pediatric scaling methods [1–6] were compared and summarized in decision tables for pediatric scaling. Due to their ease of implementation, it was first assessed when allometric scaling with a fixed exponent of 0.75 (AS0.75) [1] and/or linear bodyweight-based scaling (linearBW) [2] systematically yield accurate clearance predictions. The scaling is considered systematically accurate when the prediction error (PE) between scaled and PBPK-predicted pediatric clearance is 50% or less for all drugs in the analysis. In case neither of these allometric methods were systematically accurate, it was evaluated whether one of three other scaling methods ((age-dependent exponent (ADE) scaling [4], fixed allometric scaling with maturation function based on an enzyme maturation function used in the PBPK models (AS0.75×MFPBPK) [4], and/or between-drug extrapolation of pathway-specific pediatric covariate functions (BEPC)) [3] are systematically accurate and therefore a priori acceptable as pediatric scaling method.

Results: The pediatric decision tables show that for children older than five years, both AS0.75 and linearBW scaling can be used to scale clearance for all drugs with slight differences in accuracy depending on age and drug properties, since scaled pediatric clearance values appeared hardly sensitive to the allometric exponent in this age-range. In children below five years, additional information regarding drug properties (i.e. elimination route, binding plasma protein, fraction unbound, and/or extraction ratio) and age are required before it can be decided which scaling method is most appropriate. By using the decision tables for pediatric scaling, the need for full PBPK modelling to predict drug clearance in pediatrics is reduced for drugs or age-ranges for which systematic accurate scaling can be achieved with allometric or other scaling methods.

Conclusions: The results show that even though allometric principles are commonly used to scale pediatric clearance, there is no universal allometric exponent (i.e., 1, 0.75 or 0.67) that can accurately scale clearance for all drugs from adults to children of all ages [1]. By unravelling the minimum amount of information required for accurate scaling of clearance from adults to children of various ages, the pediatric scaling decision tables enable to a priori select appropriate (allometric) clearance scaling methods for children, thereby reducing the need for full PBPK-based clearance predictions. 

References:

  1. Calvier EAM, Krekels EHJ, Välitalo PAJ, Rostami-Hodjegan A, Tibboel D, Danhof M, et al. Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade? Clin Pharmacokinet. 2017;56(3):273–85.
  2. Krekels EH, Calvier EA, van der Graaf PH, Knibbe CA. Children Are Not Small Adults, but Can We Treat Them As Such? CPT Pharmacometrics Syst Pharmacol. 2019;8:34–8.
  3. Calvier EAM, Krekels EHJ, Yu H, Välitalo PAJ, Johnson TN, Rostami-Hodjegan A, et al. Drugs being eliminated via the same pathway will not always require similar pediatric dose adjustments. CPT Pharmacometrics Syst Pharmacol. 2018;7(3):175–85.
  4. Calvier EAM, Krekels EHJ, Johnson TN, Rostami-Hodjegan A, Tibboel D, Knibbe CAJ. Scaling Drug Clearance from Adults to the Young Children for Drugs Undergoing Hepatic Metabolism: A Simulation Study to Search for the Simplest Scaling Method. AAPS J. 2019;21(3).
  5. Cristea S, Krekels EHJ, Allegaert K, Knibbe CAJ. The Predictive Value of Glomerular Filtration Rate-Based Scaling of Pediatric Clearance and Doses for Drugs Eliminated by Glomerular Filtration with Varying Protein-Binding Properties. Clin Pharmacokinet. 2020;59(10):1291–301.
  6. Cristea S, Krekels EHJ, Rostami-Hodjegan A, Allegaert K, Knibbe CAJ. The Influence of Drug Properties and Ontogeny of Transporters on Pediatric Renal Clearance through Glomerular Filtration and Active Secretion: a Simulation-Based Study. AAPS J. 2020;22(4):87.
  7. 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 Jan;

Reference: PAGE 30 (2022) Abstr 10159 [www.page-meeting.org/?abstract=10159]

Poster: Drug/Disease Modelling - Paediatrics