Prediction of Clearance in Children Using a Combined Physiology-based and Enzyme Ontogeny Approach

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Objective: Clearance is a critical pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Clearance in children is dependent upon the physiological maturity and enzymatic ontogeny of the responsible elimination processes. This study aimed to predict clearance through the scaling of various individual elimination pathways in the age range from premature neonates to sub-adults.

Methods: Accurate clearance scaling to children requires prior knowledge of adult clearance and the age-dependence of physiological and enzymatic development. Using experimental adult and children clearance values for eight single elimination pathway compounds plus in vitro data, a model for the ontogeny of renal clearance (glomerular filtration and tubular secretion), CYP3A4, CYP2E1, CYP1A2, UGT2B7, UGT1A6, sulfonation and biliary clearance was developed. Six compounds that demonstrate multiple pathways of elimination were used to test the ontogeny models. Each pathway was individually scaled to the desired age inclusive of protein binding prediction and summed to generate a total plasma clearance.

Results: Although interindividual variability was higher in studies using children in comparison to adult data, the age-dependence of clearance of all processes followed a similar pattern. Clearance in premature neonates was usually much lower than the adult clearance. With proceeding maturation, weight normalized clearance in children exceeded that in adults and gradually reached adult levels in the early 20’s. There was excellent correlation between experimental and predicted clearances for the training (R² = 0.957) and test sets (Q² = 0.854). Clearance in premature neonates could also be well predicted (training R² = 0.921; test Q² = 0.810).

Conclusion: Using this information, the scaling of clearance to children would be a first step towards the development of dosing regimes for clinical trials in children and for examining the developmental extent of drug-drug interactions in paediatric patients.