Ontogeny of hepatic and renal systemic clearance pathways in infants: part II.

Maturation of drug systemic clearance mechanisms during the postnatal period produces dramatic and rapid changes in an infant's capacity to eliminate drugs. A tentative general mathematical model describing the ontogeny of hepatic cytochrome P450 (CYP) enzyme-mediated clearance and renal clearance due to glomerular filtration in the first 6 months of life was elaborated from age-specific in vitro hepatic microsomal activity data (normalised to amount of hepatic microsomal protein) for enzyme-specific probe substrates and in vivo probe substrate data for glomerular filtration (normalised to bodyweight), respectively. The model predicts an age- and clearance pathway-specific Infant Scaling Factor (ISF) for the first 6 months of life. The ISF reflects functional maturation of a specific clearance pathway (normalised to bodyweight) relative to adult values. Therefore, the ISF directly correlates adult clearance values with an infant's capacity to eliminate drugs. Substitution of appropriate model parameter estimates and the age of the infant into the model provides an estimated ISF value, which may then be used to predict the contribution of a particular clearance pathway to total systemic clearance in the infant when adult systemic clearance values are known. The model was tested for its ability to predict infant systemic clearance of drugs whose elimination is principally mediated by a single CYP enzyme or by glomerular filtration. The model performed reasonably well for CYP1A2 and CYP3A4, but poorer predictions were obtained for CYP2D6 and CYP2C because of lack of model complexity and/or inadequate hepatic microsomal activity data to fully describe the maturational process of functional enzyme. For renal clearance due to glomerular filtration, data normalised to bodyweight (kg) showed a limited maturational trend, suggesting that adult renal clearances normalised to bodyweight might reasonably predict infant renal clearances in the first 6 months of life. The model provided reasonable predictions of renal clearance due to glomerular filtration in the infant.