Date Published: June 21, 2020
Publisher: Springer International Publishing
Author(s): Sînziana Cristea, Elke Henriëtte Josephina Krekels, Amin Rostami-Hodjegan, Karel Allegaert, Catherijne Annette Jantine Knibbe.
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.
Between 21 and 31% of marketed drugs are primarily renally cleared . Processes underlying renal clearance (CLR) include glomerular filtration (GF), active tubular secretion (ATS), reabsorption, and renal metabolism. Maturation of GF has been extensively studied and quantified in children. However, less is known about the impact of maturation in the other process on CLR, partly due to the lack of specific biomarkers to distinguish between the activity of different transporters and to the overlap in specificity of transporters for different substrates Together with GF, ATS is one of the major contributing pathways for CLR; ontogeny of ATS is therefore the focus of the current analysis.
A PBPK-based framework was used to predict CLR of hypothetical drugs with various properties that are substrates for renal secretion transporters throughout the pediatric age range. This approach provided insight on the contribution of GF and ATS to the total pediatric CLR. In addition, the impact of ignoring this transporter ontogeny in predicting CLR in children was quantified.
A PBPK-based framework was used to determine the role of drug properties and ontogeny of transporters in predicting pediatric CLR. The contribution of GFR to CLR is influenced by drug fu. The contribution of ATS to CLR is predominantly influenced by changes in fu and CLint,T for drugs with low and medium CLint,T as well as by changes in QR for drugs with high CLint,T. Transporters play a major role in predicting CLR. Discordance in the CLR predictions when ignoring maturation in ATS shows when acceptable predictions of total pediatric CLR from the adults if extrapolation solely relied on changes in GF with age are not possible. Ignoring transporter ontogeny, especially when it is below 0.2 of the adult values, leads to unacceptable CLR predictions for the majority of drugs, regardless of age. Given known age-dependent patterns, transporter ontogeny cannot be ignored in children younger than 2 years. Drugs with properties that lead to high %PD when ignoring ATS ontogeny may serve as sensitive in vivo probes to further investigate transporter ontogeny.