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

S Cristea, EHJ Krekels, K Allegaert, CAJ Knibbe*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)
9 Downloads (Pure)

Abstract

Introduction:

For drugs eliminated by glomerular fltration (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 diferent protein-binding properties.

Methods:

First, diferent 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 profles, 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.
Original languageEnglish
Pages (from-to)1291-1301
Number of pages11
JournalClinical Pharmacokinetics
Volume59
Issue number10
DOIs
Publication statusPublished - 21 Apr 2020

Bibliographical note

Funding:

Catherijne A.J. Knibbe received support from the Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Dutch
Organization for Scientifc Research (NWO) for the submitted work.

Research programs

  • EMC OR-01

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