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Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous Suspension Is Highly Dependent on the Study Dosing Conditions

  • Research Article
  • Theme: Use of PBPK Modeling to Inform Clinical Decisions: Current Status of Prediction of Drug-Food Interactions
  • Published:
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Abstract

Extending licensed drug use to the pediatric population has become an essential part of the drug development process. Nonetheless, ethical concerns limit clinical testing in pediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the target pediatric (sub)populations. However, based on published information, food effects on drug absorption in infants may not be adequately evaluated by data collected in adults. In the present study, a physiologically based pharmacokinetic (PBPK) approach for modeling paracetamol suspension data collected in adults was proposed with the ultimate aim to investigate whether extrapolation to infants is substantially affected by the dosing conditions applied to adults. The development of the PBPK model for adults was performed using GastroPlus™ V9.7, and after scaling to infants considering physiological, anatomical, and drug clearance changes, extrapolation of the different dosing conditions was performed by applying dosing conditions dependent on changes on the paracetamol gastric emptying process. Successful simulations of previously observed plasma concentration levels in infants were achieved when extrapolating from fasted and infant formula–fed conditions data. Data collected following the reference meal appeared less useful for simulating paracetamol suspension performance in infants. The proposed methodology deserves further evaluation using high-quality clinical data both in adults and in infants.

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Acknowledgments

The authors would like to express their gratitude to SimulationsPlus Inc. for their support and providing access to the latest software version of the PBPK modeling platform GastroPlus™ 9.7.

Funding

This work has received funding from Horizon 2020 Marie Sklodowska-Curie Innovative Training Networks programme under grant agreement no. 674909.

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Authors and Affiliations

  1. Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 157 84 Zografou, Athens, Greece

    Marina Statelova, Christos Reppas & Maria Vertzoni

  2. Drug Product Development, Janssen Research and Development, Johnson & Johnson, Beerse, Belgium

    René Holm

  3. Department of Science and Environment, Roskilde University, 4000, Roskilde, Denmark

    René Holm

  4. Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

    Nikoletta Fotaki

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  1. Marina Statelova
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Statelova, M., Holm, R., Fotaki, N. et al. Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous Suspension Is Highly Dependent on the Study Dosing Conditions. AAPS J 22, 126 (2020). https://doi.org/10.1208/s12248-020-00504-6

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