Drugs Being Eliminated via the Same Pathway Will Not Always Require Similar Pediatric Dose Adjustments

Abstract

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between‐drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month.

AssessingCYP2C19 Ontogeny in Neonates and Infants Using Physiologically Based Pharmacokinetic Models: Impact of Enzyme Maturation Versus Inhibition

“…However, the esomeprazole PBPK model with CYP2C19 auto‐inhibition significantly underpredicted CL in the younger age group of pediatric patients, especially in neonates. The differences in PBPK model predictive performance for the two drugs suggest the difficulty in the extrapolation of PK models between drugs sharing an elimination pathway . The PBPK model with CYP2C19 auto‐inhibition for esomeprazole, which has been verified in adults and older children, could not be directly extrapolated to neonates/infants.…”

“…The differences in PBPK model predictive performance for the two drugs suggest the difficulty in the extrapolation of PK models between drugs sharing an elimination pathway. 43 The PBPK model with CYP2C19 auto-inhibition for esomeprazole, which has been verified in adults and older children, could not be directly extrapolated to neonates/infants. A good model prediction requires a thorough understanding of the complex interplay between CYP maturation and inhibition in infants.…”

Ontogeny of Phase I Metabolism of Drugs

“…This better performance was observed for both intravenous (100% instead of 51% of the predictions within the 2‐fold range) and oral (98% instead of 67% within the 2‐fold range) dosing . Crucial for pediatric drug development and along the same line of proof of concept of extrapolation of pediatric covariates functions, Calvier et al explored the similarity of pediatric dose adjustments for drugs being eliminated via the same hepatic metabolic clearance pathway, using a PBPK workflow. Interestingly, the similarity of “proportional dose adaptations” was dependent on the drug extraction ratio, the unbound fraction, the type of plasma protein binding, and the fraction metabolized by the specific isoenzyme pathway.…”

“…Interestingly, the similarity of “proportional dose adaptations” was dependent on the drug extraction ratio, the unbound fraction, the type of plasma protein binding, and the fraction metabolized by the specific isoenzyme pathway. Performance was best with low and intermediate extraction ratio drugs, eliminated by a single isoenzyme, albumin bound, with underperformance in neonates …”

“…Performance was best with low and intermediate extraction ratio drugs, eliminated by a single isoenzyme, albumin bound, with underperformance in neonates. 29…”