The impact of renal transporters on paediatric renal clearance
S Cristea (1), EAM Calvier (1), A Rostami-Hodjegan (2,3), EHJ Krekels (1), CAJ Knibbe (1,4)
(1) Division of Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, The Netherlands, (2) Simcyp (A Certara Company), Blades Enterprise Centre, Sheffield, UK, (3) Manchester Pharmacy School, Manchester University, Manchester, UK, (4) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Although transporters hold a key role in drug disposition, their impact on renal clearance (CLR) has been less studied, particularly in children[1]. Using physiologically-based simulations, we investigate the impact of physiological changes, transporters activity (CLs,int) and their ontogeny on CLR.
Methods: Using R, we generated virtual paediatric individuals to simulate CLR of hypothetical drugs with low, median and high reference unbound fractions (fu-HSA). CLR simulations were based on a model that comprises glomerular filtration and active tubular secretion[2]. Ontogeny of fu-HSA[3], renal blood flow[4], kidney size[5], and glomerular filtration[6] was implemented based on literature. The contribution of active tubular secretion to CLR was assessed for a CLs,int range in adults between 2-250 µL/min, representing one or more transporters. For transporters ontogeny, percentages between 50 and 200% of CLs,int adult values were tested. The impact of ontogeny on CLR for each age was expressed as a percentage difference compared to 100% CLs,int for that specific age.
Results: Glomerular filtration and active tubular secretion changed proportionally with fu-HSA. The impact of active tubular secretion on CLR was influenced by age-related physiological changes. For a CLs,int of 50 µL/min, the contribution of active tubular secretion to CLR varied between 25-39% due to variation in renal blood flow and kidney size. In the studied CLs,int range we showed that a 5-fold increase in CLs,int yielded a 2-fold increase in contribution of active tubular secretion to CLR. The impact on CLR of ontogeny in CLs,int, expressed as a percentage difference compared to 100% CLs,int, decreased with age, i.e., for an enhanced transporter activity of 200%, the percentage difference decreased from 15% in a 1 day old neonate to 9% in adults.
Conclusions: In the present work, we established the variables that impact CLR in the context of physiological changes and transporter ontogeny in children. Throughout the studied age range, glomerular filtration is the main driver of renal clearance unless multiple transporters contribute to active tubular secretion which could result in a contribution of up to 73%.
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