Scaling Drug Clearance from Adults to the Young Children for Drugs Undergoing Hepatic Metabolism: A Simulation Study to Search for the Simplest Scaling Method.

ABSTRACT

Previous research showed that scaling drug clearance from adults to children based on body weight alone is not accurate for all hepatically cleared drugs in very young children. This study systematically assesses the accuracy of scaling methods that, in addition to body weight, also take age-based variables into account for drugs undergoing hepatic metabolism in children younger than five years, namely scaling with (1) a body weight-based function using an age-dependent exponent (ADE) and (2) a body weight-based function with fixed exponent of 0.75 (AS0.75) combined with isoenzyme maturation functions (MFPBPK) similar to those implemented in physiologically based pharmacokinetic (PBPK) models (AS0.75 + MFPBPK). A PBPK-based simulation workflow was used, including hypothetical drugs with a wide range of properties and metabolized by different isoenzymes. Adult clearance values were scaled to seven typical children between one day and four years. Prediction errors of ± 50% were considered reasonably accurate. Isoenzyme maturation was found to be an important driver of changes in hepatic metabolic clearance in children younger than five years, which prevents the systematic accuracy of ADE scaling. AS0.75 + MFPBPK, when accounting for maturation of isoenzymes and microsomal protein per gram of liver (MPPGL), can reasonably accurately scale hepatic metabolic clearance for all low and intermediate extraction ratio drugs except for drugs binding to alpha-1-acid glycoprotein in neonates. As differences in the impact of changes in system-specific parameters on drugs with different properties yield differences in clearance ontogeny, it is unlikely that for the remaining drugs, scaling methods that do not take drug properties into account will be systematically accurate.