A Retrospective Evaluation of Allometry, Population Pharmacokinetics, and Physiologically-Based Pharmacokinetics for Pediatric Dosing Using Clearance as a Surrogate.

Physiologically-based pharmacokinetic models are increasingly applied for pediatric dose selection along with traditional methods such as allometry and population pharmacokinetic models. We report a retrospective evaluation of the three methods. Pediatric population pharmacokinetic models sourced from literature for a subset of eight compounds were used to predict clearances for children < 2 years when they were within the modeled age range (interpolation, N = 11) or including those outside the modeled 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 twofold criteria. For children > 2 years, 58-75% of the clinical studies (N = 10) met the strict criteria, and > 80% of the clinical studies were predicted within twofold by all three methods. For children < 2 years, physiologically-based pharmacokinetic, allometry with age-dependent exponents, and pediatric population pharmacokinetic models predict 54%, 82%, and 64% within twofold of the observed, respectively.