A Retrospective Evaluation of Allometry, Population PK and PBPK for Pediatric Dosing using Clearance as a Surrogate.

Physiologically-based pharmacokinetic (PBPK) models are increasingly applied for pediatric dose selection along with traditional methods such as allometry and population pharmacokinetic (popPK) models. Here, we report a retrospective evaluation of the three methods. Pediatric popPK models sourced from literature for a subset of 8 compounds, were used to predict clearances for children <2 years when they were within the modelled age range (interpolation, N = 11) or including those outside the modelled age range (interpolation and extrapolation, N = 18). Pediatric/adult clearance ratios were evaluated with a strict performance criterion of 0.8-1.25, and with 2-fold criteria. For children >2 years, 58 - 75% of the clinical studies (N = 10) met the strict criteria, >80% of the clinical studies were predicted within 2- fold by all 3 methods. For children <2 years, PBPK, allometry with age-dependent exponents (ADE) and pediatric popPK models predict 54%, 82% and 64% within 2-fold of the observed respectively. This article is protected by copyright. All rights reserved.