World Health Organisation paediatric dosing tool

A paediatric dosing tool developed by World Health Organisation (WHO) might assist in the design of clinical trials for dosing in children.

When finding a safe and effective dose for children, the approach in anti-infectives is to target drug exposures similar to those in successfully treated adults. Scaling pharmacokinetics (PK) is the first step.

Down to two or three years of age, body size accounts for most of the differences in doses between children and adults.

The paediatric dosing tool – developed by the WHO Paediatric ARV Working Group (PAWG) – uses allometric scaling to help evaluate antiretroviral dosing regimens. The WHO paediatric dosing tool was presented at CROI 2017.

Allometric scaling describes the nonlinear effect of body size on PK parameters. A milligram per kilogram (mg/kg) dose in children and adults causes under-dosing in children. Even without other available information, allometry is a better guess than constant mg/kg. But paediatric dosing regimens still use constant mg/kg dosing as first best guess.

The objective of the work by the PAWG is to bridge this gap. WHO proposes an easy-to-use tool to assist researchers not familiar with PK modelling to design and evaluate paediatric dosing regimens.

The tool operates in Microsoft Excel and has easy steps to follow with results displayed in real time. It uses allometric scaling to adjust for the effect of a child’s body size on clearance and it targets the same area under the time-concentration curve (AUC) as that for adults. The lowest and highest values within a paediatric weight band are shown alongside the target.

The tool can also analyse multiple drugs in a fixed dose combination and used either standarised or customised weight bands. If the effect of maturation is known for a drug this can be specified.

The WHO group note that allometric scaling alone only works well down to two years of age. Below that immature organ function could mean that clearance might be lower than that predicted using only body size. This is specific to individual drugs. Other unaccounted for factors might also have an impact: lower protein binding in children; drug formulation differences; and poor absorption.

Another limitation is that terminal half-life is usually shorter in children so adult AUC targets might lead to higher Cmax and lower Cmin so it might be necessary to dose smaller children twice daily.

The group stress that the tool is to support the design of clinical trials for dosing in paediatrics and is “not a substitute for confirmatory studies”. They add that the use of the tool in study design “would represent a significant step away from the constant mg/kg paradigm, possibly leading to improvements in the efficacy of paediatric dosing trials”.