Children Are Not Small Adults, but Can We Treat Them As Such?

Abstract

Although children cannot be considered small adults due to nonlinear processes underlying the pharmacokinetics of drugs, pediatric doses are typically still expressed per kilogram. We use a physiologically based pharmacokinetic (PBPK) workflow to assess the accuracy of linear scaling of plasma clearance (CLp) for hypothetical drugs with ranges of realistic parameter values in pediatric patients of different ages. The results are compared with 0.75 fixed allometric scaling (AS 0.75). Linear CLp scaling is accurate down to the age of 1 month for drugs undergoing glomerular filtration, except when these drugs are highly bound to alpha-1-acid glycoprotein (AGP). For hepatically cleared drugs, linear scaling is reasonably accurate down the age of 2 years, except for AGP-bound drugs with a low extraction ratio and mature isoenzymes. In neonates, linear scaling outperforms AS 0.75 for human serum albumin (HSA) and AGP-bound drugs excreted through glomerular filtration. These results suggest that pediatric patients can, in many cases, be treated as small adults.

Figure 1

Prediction error for linearly scaled CLp values for hypothetical drugs undergoing hepatic metabolism, binding to various extends to alpha‐1‐acid glycoprotein (AGP, dark colors) or human serum albumin (HSA, light colors) and having low (pink), intermediate (blue), or high (green) extraction ratio. At the top row, results are shown for scenarios in which enzyme maturation is 100%of adult values, the bottom and middle row show results for the lowest and highest reported enzyme maturation value for each age, respectively, which were 10% and 100% at 1 day and 1 month, 25% and 122% at 6 months, 35% and 153% at 1 year, 57% and 159% at 2 years, 71% and 152% at 5 years, and 90% and 125% at 15 years. Black and red vertical dotted lines correspond to an absolute prediction error of 30 and 50% respectively.