Anne van Rongen1, Robbin Grijseels1, Elisa A.M. Calvier2, Karel Allegaert3,4,5, Catherijne A.J. Knibbe1,6, Elke Krekels1,7
1Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, 2Pharmacokinetics-Dynamics and Metabolism, Translational Medicine and Early Development, Sanofi R&D, 3Department of Development and Regeneration, KU Leuven, 4Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 5Department of Hospital Pharmacy, Erasmus MC, 6Department of Clinical Pharmacy, St. Antonius Hospital, 7Certara Inc.
Objectives In the absence of clinical data, common pediatric clearance (CL) scaling approaches rely on maturation functions for the dominant elimination route in adults, but this does not consider that minor CL pathways may take over in children when the major pathway is still immature. We explore whether hepatic metabolism can be assumed to remain the dominant CL pathway in children younger than 4 years of age for drugs that are predominantly cleared through hepatic metabolism in adults. Methods A PBPK-based simulation framework was developed in R (v4.4.3). The dispersion model quantified drug CL through hepatic metabolism (CLh) based on unbound drug fraction (fu), whole-liver intrinsic clearance (CLint), blood-to-plasma ratio (B:P), and hepatic blood flow (Qh). CL through glomerular filtration (CLGF) was obtained by multiplying glomerular filtration rate (GFR) with fu. Simulations were performed for 460 hypothetical drugs that either exclusively bind to human serum albumin (HSA) or a1-acid glycoprotein (AGP) with an affinity that led to an fu in the typical adult of 1%, 25%, 50%, 75%, or 99%. For each drug, the intrinsic microsomal clearance (CLint,mic) was selected to be such that total plasma CL in the typical adult comprised 90% or 70% hepatic metabolism and 10% or 30% GF, respectively. The partitioning coefficient (Kp), which drives B:P, was set to 1 for all drugs. One scenario investigated each drug to be a substrate of each of six hypothetical isoenzymes with a constant maturation of 100%, 75%, 50%, 25%, 10%, 5%, or 0.5% across all seven pediatric ages. In a second scenario, each drug was substrate of each of the following isoenzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, SULT1A1, UGT1A1, UGT1A4, UGT 1A6, UGT1A9, or UGT2B7. CLh and CLGF were simulated for a typical adult of 25 years and for typical pediatric individuals aged one day, two weeks, one month, six months, or one, two, or four years. Equations to derive pediatric values for the system-specific model parameters were taken from Johnson et al. [1]. Results For substrates of an isoenzyme that is mature at birth, maturational changes in all other system-specific parameters (i.e., GFR, Qh, hematocrit, liver weight, and microsomal protein per gram of liver) yield a contribution of hepatic metabolism that slightly exceeds the adult value at birth, while between the ages of 6 months and 4 years the relative hepatic metabolic contribution drops by 10-20% before returning to adult values. For drugs with CLh of 90% in adults, the contribution of hepatic metabolic clearance to total plasma clearance in children is lower for drugs with higher protein binding, while this effect is negligible for drugs with CLh in adults of 70%. When CLh comprises 90% of adult CL, hepatic metabolism remains dominant even when enzyme maturation is 25%. At 10% enzyme maturation, GF is dominant in children between 6 months and 4 years, while GF is the dominant elimination route for all drugs in all ages below 4 years only at 5% enzyme maturation. When CLh comprises 70% of adult CL, GF is dominant in children between 6 months and 4 years when enzyme maturation is lower than 75%, while at an enzyme maturation of 25%, GF is dominant in all ages below 4 years. For substrates of most studied isoenzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP3A4, SULT1A1, UGT1A4, UGT1A6, and UGT1A9) hepatic metabolism will remain the dominant pathway in children, irrespective of the degree of protein binding or the plasma protein the drug binds to, when CLh comprises 90% of adult CL. However, when CLh comprises 70% of adult CL, hepatic metabolism will only remain dominant throughout childhood for substrates of CYP2C8, CYP2C9, and SULT1A1. Conclusions When hepatic metabolism comprises 90% of total adult plasma clearance, hepatic metabolism remains the dominant route of elimination throughout childhood for substrates of most, but not all, isoenzymes. However, when hepatic metabolism in adults comprises 70% of total plasma clearance, hepatic metabolism will not remain dominant for at least part of the pediatric age-range for substrates of most, but not all, isoenzymes. In scenarios where hepatic metabolism is not dominant, scaling for the dominant CL route in adults will likely yield underprediction of total plasma clearance and the contribution of alternative routes needs to be taken into account.
[1] Johnson TN et al. Clin Pharmacokinet. 2006;45(9):931-56.
Reference: PAGE 33 (2025) Abstr 11515 [www.page-meeting.org/?abstract=11515]
Poster: Drug/Disease Modelling - Paediatrics