Changes in the Fraction Metabolized in Children Younger than Four Years; When is Clearance Scaling for the Dominant Elimination Route in Adults Appropriate?

introductionA common approach to scaling clearance from adults to children is to apply a maturation function for the dominant elimination pathway in adults. We investigate for drugs mainly cleared through hepatic metabolism, how the fraction metabolized changes and whether this pathway remains dominant in young children.

methodsA physiologically-based pharmacokinetic workflow was developed investigating 460 hypothetical drugs that were for 90% or 70% cleared through hepatic metabolism in adults with remaining clearance through glomerular filtration. Their unbound drug fractions were between 1 and 99% and they were metabolized by isoenzymes with different maturation patterns. Absolute and relative clearance through hepatic metabolism was calculated in a typical adult and seven typical pediatric individuals younger than 4 years.

resultsWhen hepatic metabolism comprises 90% of total plasma clearance in adults, it tends to remain the dominant elimination route throughout childhood for substrates of all isoenzymes, except for substrates of CYP2A6, UGT1A1, and UGT2B7. However, when hepatic metabolism comprises 70% of the total plasma clearance in adults, hepatic metabolism will not remain dominant for at least part of the pediatric age-range for substrates of many enzymes, except for substrates of CYP2C8, CYP2C9, and SULT1A1.

conclusionThis study identified scenarios in which hepatic metabolism cannot be assumed to remain dominant in children younger than 4 years, when it is the dominant elimination route in adults. In these scenarios, scaling for the dominant clearance route in adults will yield underprediction of total plasma clearance and the contribution of alternative routes needs to be considered.