A Novel Maturation Equation for Hepatic Clearance Across Preterm, Term Neonates, Children, and Adults: Application to Paracetamol and Its Metabolite

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Abstract A preterm and term neonate to adult (PTNA) maturation equation was introduced recently to describe the glomerular filtration rate maturation from birth to adulthood for neonates of varying gestational age. This study aims to evaluate the newly developed PTNA equation against common maturation approaches like allometric scaling (AS0.75), the AS0.75 plus postmenstrual age (PMA)‐based E max (AS0.75 + PMA) equation, and the bodyweight dependent exponent equation (BDE) for the maturation of three hepatic pathways of paracetamol (PCM) from preterm and term neonates up to adults. A population pharmacokinetic analysis was conducted with pooled plasma and urine data of PCM, PCM‐glucuronide (PCM‐GLU), PCM‐sulfate (PCM‐SULF), and PCM‐oxidative metabolites (PCM‐OXI) (number of observations:6428) from 298 subjects, including preterm and term neonates, infants, children, and adults. PTNA, AS0.75, AS0.75 + PMA, and BDE were evaluated separately to describe the formation clearance of each PCM metabolite. Results indicated that the PTNA equation best described the formation clearance of PCM‐GLU, outperforming the BDE and AS0.75 + PMA equations in both statistical and graphical evaluation metrics and inter‐individual variability reduction. For PCM‐SULF and PCM‐OXI, the PTNA equation also had the best performance, but the improvements were smaller. The final model described the PK of PCM and its metabolites adequately among subpopulations as indicated by diagnostic plots. In conclusion, the PTNA maturation equation best describes the maturation of all hepatic elimination pathways of PCM. It can, as such, be potentially applied to other drugs and pathways when data from both preterm and term neonates and older children are part of the PK analysis.

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