Use of Clinical Trial Simulations to Compare the Performance of Different Approaches for Population Analyses of Pediatric Pharmacokinetic Data.

Adequate characterization of the pharmacokinetics of a drug in pediatrics is mainstay to pediatric development programs and is critical for accurate dose selection in pediatrics. Analysis approaches can impact estimation and characterization of pediatric pharmacokinetic parameters. Analyses were conducted to compare performance of different approaches for analysis of pediatric pharmacokinetic data in the presence of extensive data from adult studies. Simulated clinical trial datasets were generated encompassing different scenarios which might be encountered in pediatric drug development. For each scenario, 250 clinical trials were simulated and analyzed using each of the following approaches: 1) estimating pediatric parameters using only pediatric data, 2) fixing specific parameters to adult estimates and estimating the remaining pediatric parameters using only pediatric data, 3) estimating pediatric parameters using adult parameters as informative Bayesian priors, 4) estimating pediatric parameters using combined adult and pediatric datasets with exponents for weight and clearance estimated using adult and pediatric data 5) estimating pediatric parameters using combined adult and pediatric datasets with exponents for weight and clearance estimated using pediatric data only. Each analysis approach was evaluated for its success in estimation of true pediatric pharmacokinetic parameter values. Results demonstrated that analyzing pediatric data using a Bayesian approach generally performed best and had the lowest probability of significant bias in the estimated pediatric pharmacokinetic parameters amongst different scenarios evaluated. This clinical trial simulation framework can be used to inform the optimal approach for analyses of pediatric data for other pediatric drug development program scenarios beyond the cases evaluated in these analyses. This article is protected by copyright. All rights reserved.