PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure
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. PBP...
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MDPI AG
2025-07-01
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| author | Sonia Sharma David R. Taft |
| author_facet | Sonia Sharma David R. Taft |
| author_sort | Sonia Sharma |
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| description | 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<sup>®</sup> 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. |
| format | Article |
| id | doaj-art-eada1ba04fb74a0eaecf270e9775557c |
| institution | Kabale University |
| issn | 2075-1729 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-eada1ba04fb74a0eaecf270e9775557c2025-08-20T03:36:21ZengMDPI AGLife2075-17292025-07-01157109910.3390/life15071099PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic ExposureSonia Sharma0David R. Taft1Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USASamuel J. and Joan B. Williamson Institute for Pharmacometrics, Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USASulfotransferase (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<sup>®</sup> 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.https://www.mdpi.com/2075-1729/15/7/1099PBPK modelingacetaminophenpediatricsSULTontogenyneonates |
| spellingShingle | Sonia Sharma David R. Taft PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure Life PBPK modeling acetaminophen pediatrics SULT ontogeny neonates |
| title | PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure |
| title_full | PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure |
| title_fullStr | PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure |
| title_full_unstemmed | PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure |
| title_short | PBPK Modeling of Acetaminophen in Pediatric Populations: Incorporation of SULT Enzyme Ontogeny to Predict Age-Dependent Metabolism and Systemic Exposure |
| title_sort | pbpk modeling of acetaminophen in pediatric populations incorporation of sult enzyme ontogeny to predict age dependent metabolism and systemic exposure |
| topic | PBPK modeling acetaminophen pediatrics SULT ontogeny neonates |
| url | https://www.mdpi.com/2075-1729/15/7/1099 |
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