A comparison of different methods for the first-in-pediatric dose selection

Abstract

Background and aim: To conduct a pediatric clinical trial, it is important to optimize pediatric dose as accurately as possible. This is mainly because due to ethical reasons, children cannot be given several doses to evaluate pharmacokinetics, safety, and efficacy of a drug.

Methods: In this study, several simple methods to project a first-in-pediatric dose to initiate a clinical trial were evaluated. These methods were as follows:(1) Weight-based pediatric dose prediction (allometric scaling), (2) Salisbury rule (weight-based method), and (3) pediatric dose prediction based on predicted clearance. These methods were compared with the dose given to children in clinical practice. The methods were also compared with whole-body physiologically based pharmacokinetic (PBPK) model (n = 11). A ±30% prediction error (predicted vs. observed) was considered acceptable.

Results: There were 27 drugs with 113 observations (different age groups from preterm neonates to adolescents). At least, ≤30% prediction error in pediatric dose projection was noted for more than 70% observations. The predictive performance of all the proposed methods was comparable with the whole-body PBPK.

Conclusions: The proposed methods are simple and accurate and can be developed on a spreadsheet in a very short period of time.

Relevance for patients: The study provides an estimate of first-in-pediatric dose by simple methods to initiate pediatric clinical trials. Especially, Salisbury rule is based on body weight and is very simple and works fairly well in children >30 kg body weight and can be even used in clinical settings.

Keywords: Salisbury rule; age-dependent exponents; body weight; dose; whole-body physiologically based pharmacokinetic.