Changes in the Fraction Metabolized in Children Younger than Four Years; When is Clearance Scaling for the Dominant...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pediatric Pharmacology
• Physiologically-Based Pharmacokinetic (PBPK) Modeling

Background:

• Scaling drug clearance from adults to children often assumes the dominant adult elimination pathway remains dominant in pediatric populations.
• This approach may be inaccurate for drugs primarily cleared by hepatic metabolism, as its dominance can change in young children.

Purpose of the Study:

• To investigate the changes in the fraction of hepatic metabolism and its dominance in young children for drugs primarily cleared hepatically in adults.
• To identify scenarios where hepatic metabolism may not remain the dominant elimination route in pediatric populations.

Main Methods:

• Development of a physiologically-based pharmacokinetic (PBPK) workflow.
• Simulation of 460 hypothetical drugs with varying fractions of hepatic metabolism (90% or 70%) and unbound fractions.
• Calculation of absolute and relative hepatic clearance in adult and pediatric individuals (<4 years) for various isoenzymes with different maturation patterns.

Main Results:

• When hepatic metabolism accounts for 90% of adult clearance, it generally remains dominant in children, except for substrates of CYP2A6, UGT1A1, and UGT2B7.
• When hepatic metabolism is 70% in adults, it often ceases to be dominant in pediatric populations for substrates of many enzymes, with exceptions like CYP2C8, CYP2C9, and SULT1A1.

Conclusions:

• Hepatic metabolism dominance in adults does not guarantee it in children under 4 years.
• Alternative elimination routes must be considered in pediatric drug development when hepatic metabolism is not consistently dominant, to avoid underpredicting total plasma clearance.