The Predictive Value of Glomerular Filtration Rate-Based Scaling of Pediatric Clearance and Doses for Drugs Eliminated b
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ORIGINAL RESEARCH ARTICLE
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 Sinziana Cristea1 · Elke H. J. Krekels1 · Karel Allegaert2,3,4 · Catherijne A. J. Knibbe1,5
© The Author(s) 2020
Abstract Introduction For drugs eliminated by glomerular filtration (GF), clearance (CL) is determined by GF rate (GFR) and the unbound fraction of the drug. When predicting CL of GF-eliminated drugs in children, instead of physiologically based pharmacokinetic (PBPK) methods that consider changes in both GFR and protein binding, empiric bodyweight-based methods are often used. In this article, we explore the predictive value of scaling using a GFR function, and compare the results with linear and allometric scaling methods for drugs with different protein-binding properties. Methods First, different GFR maturation functions were compared to identify the GFR function that would yield the most accurate GFR predictions across the pediatric age range compared with published pediatric inulin/mannitol CL values. Subsequently, the accuracy of pediatric CL scaling using this GFR maturation function was assessed and compared with PBPK CL predictions for hypothetical drugs binding, to varying extents, to serum albumin or α-acid glycoprotein across the pediatric age range. Additionally, empiric bodyweight-based methods were assessed. Results The published GFR maturation functions yielded comparable maturation profiles, with the function reported by Salem et al. leading to the most accurate predictions. On the basis of this function, GFR-based scaling yields reasonably accurate (percentage prediction error ≤ 50%) pediatric CL values for all drugs, except for some drugs highly bound to AGP in neonates. Overall, this method was more accurate than linear or 0.75 allometric bodyweight-based scaling. Conclusion When scaling CL and dose by GFR function, maturational changes in plasma protein concentrations impact GF minimally, making this method a superior alternative to empiric bodyweight-based scaling.
Key Points Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00890-2) contains supplementary material, which is available to authorized users. * Catherijne A. J. Knibbe [email protected] 1
Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
2
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
3
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
4
Clinical Pharmacy, Erasmus MC Rotterdam, Rotterdam, The Netherlands
5
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
A maturation function for glomerular filtration is preferred for scaling clearance (CL) and doses from adults to the pediatric population over empiric bodyweightbased methods. Maturation
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