The Influence of Drug Properties and Ontogeny of Transporters on Pediatric Renal Clearance through Glomerular Filtration and Active Secretion: a Simulation-Based Study

Abstract

Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CLR for drugs with different properties in children. A physiology-based model for CLR in adults was extrapolated to the pediatric population by including maturation functions for the system-specific parameters. This model was used to predict GF and ATS for hypothetical drugs with a range of drug-specific properties, including transporter-mediated intrinsic clearance (CLint,T) values, that are substrates for renal secretion transporters with different ontogeny patterns. To assess the impact of transporter ontogeny on ATS and total CLR, a percentage prediction difference (%PD) was calculated between the predicted CLR in the presence and absence of transporter ontogeny. The contribution of ATS to CLR ranges between 41 and 90% in children depending on fraction unbound and CLint,T values. If ontogeny of renal transporters is < 0.2 of adult values, CLR predictions are unacceptable (%PD > 50%) for the majority of drugs regardless of the pediatric age. Ignoring ontogeny patterns of secretion transporters increasing with age in children younger than 2 years results in CLR predictions that are not systematically acceptable for all hypothetical drugs (%PD > 50% for some drugs). This analysis identified for what drug-specific properties and at what ages the contribution of ATS on total pediatric CLR cannot be ignored. Drugs with these properties may be sensitive in vivo probes to investigate transporter ontogeny.