PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure

TL;DR

This study develops a model to predict how children metabolize acetaminophen, considering enzyme development and age-related differences.

Contribution

A novel PBPK model for acetaminophen in children incorporating SULT enzyme ontogeny is developed.

Findings

SULT enzymes contribute ~60% to acetaminophen metabolism in neonates.

PBPK model accurately captures systemic exposure in neonates, infants, and children.

Model sensitivity analysis suggests potential drug-drug interactions via SULT1A1.

Abstract

Sulfotransferase (SULT) enzymes contribute significantly to drug metabolism in pediatric patients. The purpose of this study was to develop a PBPK model for acetaminophen (APAP) in pediatric populations that accounts for the ontogeny of SULT isozymes that play a critical role in APAP metabolism. PBPK modeling and simulation were performed using the Simcyp® Simulator. The model incorporated the developmental ontogeny of three key hepatic SULT enzymes: SULT1A1, SULT1A3, and SULT2A1 using “best-fit” ontogeny equations for each isozyme as determined by nonlinear regression analysis of enzyme abundance versus age. PBPK model-simulated pharmacokinetic profiles for APAP captured observed clinical data for systemic exposure (Cmax, AUC) in neonates, infants, and children. SULTS accounted for ~60% APAP metabolism in neonates, with decreased contributions to infants and children. Model sensitivity analysis highlighted the potential for APAP metabolic DDIs, primarily through SULT1A1. The study demonstrates that the impact of SULT enzymes on drug metabolism is significant in neonates, which is an important clinical consideration for APAP. A PBPK model that incorporates SULT ontogeny has the potential to help inform dosing decisions in this special patient population.

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