An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables

ABSTRACT

Introduction

When pediatric data are not available for a drug, allometric and other methods are applied to scale drug clearance across the pediatric age-range from adult values. This is applied when designing first-in-child studies, but also for off-label drug prescription.

Areas covered

This review provides an overview of the systematic accuracy of allometric and other pediatric clearance scaling methods compared to gold-standard PBPK predictions. The findings are summarized in decision tables to provide a priori guidance on the selection of appropriate pediatric clearance scaling methods for both novel drugs for which no pediatric data are available and existing drugs in clinical practice.

Expert opinion

While allometric scaling 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. Therefore, pediatric scaling decision tables based on age, drug elimination route, binding plasma protein, fraction unbound, extraction ratio, and/or isoenzyme maturation are proposed to a priori select the appropriate (allometric) clearance scaling method, thereby reducing the need for full PBPK-based clearance predictions. Guidance on allometric scaling when estimating pediatric clearance values is provided as well.

KEYWORDS:

• Allometric scaling
• body size
• clearance
• decision tables
• drug properties
• maturation
• physiologically-based pharmacokinetic
• pediatric clearance scaling

Article highlights

• We here propose pediatric scaling decision tables to provide a priori guidance on the use of linear bodyweight-based scaling (linearBW) and fixed allometric scaling with an exponent of 0.75 (AS0.75) or, when these two are both not systematically accurate, for age-dependent exponent (ADE) scaling, fixed allometric scaling with maturation function (AS0.75×MF_PBPK), and between-drug extrapolation of pathway-specific pediatric covariate functions (BEPC).

• In children >5 years, both linearBW and AS0.75 can be used to scale clearance with slight differences in accuracy depending on age and drug properties, since scaled pediatric clearance values are hardly sensitive to the allometric exponent in this age-range.

• In children <5 years, additional information regarding drug properties (i.e. elimination route, binding plasma protein, fraction unbound, and/or extraction ratio) and age is required before it can be predicted which scaling method is most appropriate.

• By using the pediatric scaling decision tables, the need for full PBPK modelling to predict drug clearance in pediatrics is reduced for drugs or age-ranges for which accurate scaling can be achieved with allometric or other scaling methods.

• Future pediatric PK studies should focus on accurate clearance predictions throughout childhood instead of identifying an allometric exponent.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary Material

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Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.