Is the GFR-based scaling approach adequate for predicting pediatric renal clearance of drugs with passive tubular reabsorption? Insights from PBPK modeling.

Abstract

Empirical maturation models (e.g., Johnson and Rhodin models) for glomerular filtration rate (GFR) are commonly used as scaling factors for predicting pediatric renal clearance, but their predictive performance for drugs featured with tubular reabsorption is poorly understood. This study investigated the adequacy of GFR-based scaling models for predicting pediatric renal clearance in drugs with passive tubular reabsorption by comparing with a mechanistic kidney model (Mech-KiM) that encompasses the physiological processes of glomerular filtration, tubular secretion, and reabsorption. The analysis utilized hypothetical drugs with varying fractions of tubular reabsorption (F_reabs), alongside the model drug metronidazole, which has a F_reabs of 96%. Our simulations showed that when F_reabs is ≤70%, the discrepancies between the GFR-based scaling methods and the Mech-KiM model in predicting pediatric renal clearance were generally within a twofold range throughout childhood. However, for drugs with substantial tubular reabsorption (e.g., F_reabs > 70%), discrepancies greater than twofold were observed between the GFR-based scaling methods and the Mech-KiM model in predicting renal clearance for young children. In neonates, the differences ranged from 5- to 10-fold when the adult F_reabs was 95%. Pediatric physiologically based pharmacokinetic (PBPK) modeling of metronidazole revealed that using a GFR-based scaling method (Johnson model) significantly overestimated drug concentrations in children under 2 months, whereas utilizing the Mech-KiM model for renal clearance predictions yielded estimates closely aligned with observed concentrations. Our study demonstrates that using GFR-based scaling models to predict pediatric renal clearance might be inadequate for drugs with extensive passive tubular reabsorption (e.g., F_reabs > 70%).