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Research ArticleArticle

Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

Sara N. Salerno, Fernando O. Carreño, Andrea N. Edginton, Michael Cohen-Wolkowiez and Daniel Gonzalez
Drug Metabolism and Disposition September 2021, 49 (9) 844-855; DOI: https://doi.org/10.1124/dmd.120.000318
Sara N. Salerno
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.)
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Fernando O. Carreño
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.)
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Andrea N. Edginton
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.)
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Michael Cohen-Wolkowiez
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.)
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Daniel Gonzalez
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.)
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Abstract

Solithromycin is a novel fluoroketolide antibiotic that is both a substrate and time-dependent inhibitor of CYP3A. Solithromycin has demonstrated efficacy in adults with community-acquired bacterial pneumonia and has also been investigated in pediatric patients. The objective of this study was to develop a framework for leveraging physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A-mediated drug-drug interaction (DDI) potential in the pediatric population using solithromycin as a case study. To account for age, we performed in vitro metabolism and time-dependent inhibition studies for solithromycin for CYP3A4, CYP3A5, and CYP3A7. The PBPK model included CYP3A4 and CYP3A5 metabolism and time-dependent inhibition, glomerular filtration, P-glycoprotein transport, and enterohepatic recirculation. The average fold error of simulated and observed plasma concentrations of solithromycin in both adults (1966 plasma samples) and pediatric patients from 4 days to 17.9 years (684 plasma samples) were within 0.5- to 2.0-fold. The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75- to 1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. DDI potential was simulated in pediatric patients (1 month to 17 years of age) and adults. Solithromycin increased the simulated midazolam AUC 4- to 6-fold, and ketoconazole increased the simulated solithromycin AUC 1- to 2-fold in virtual subjects ranging from 1 month to 65 years of age. This study presents a systematic approach for incorporating CYP3A in vitro data into adult and pediatric PBPK models to predict pediatric CYP3A-mediated DDI potential.

SIGNIFICANCE STATEMENT Using solithromycin, this study presents a framework for investigating and incorporating CYP3A4, CYP3A5, and CYP3A7 in vitro data into adult and pediatric physiologically based pharmacokinetic models to predict CYP3A-mediated DDI potential in adult and pediatric subjects during drug development. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations.

Footnotes

    • Received November 19, 2020.
    • Accepted June 2, 2021.
  • Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [Grant 5K23HD083465]. S.N.S. received financial support from the National Institute of General Medical Sciences and the NICHD [Grant T32GM086330]. F.O.C. was funded through a University of North Carolina at Chapel Hill/GlaxoSmithKline Pharmacokinetics/Pharmacodynamics Postdoctoral Fellowship. M.C.-W. received support for research from the National Institutes of Health (NIH) ([Grant 1R01-HD076676-01A1], [Grant 1K24-AI143971]), National Institute of Allergy and Infectious Diseases ([Grant HHSN272201500006I], [Grant HHSN272201300017I]), NICHD [HHSN275201000003I], US Food and Drug Administration [5U18-FD006298], and industry for drug development in adults and children. D.G. received research support from the NICHD ([Grant 5K23HD083465], [Grant 5R01HD096435-03], and [Grant 1R01HD102949-01A1]).

  • M.C.-W. and D.G. have previously received research support for solithromycin drug development research sponsored by the US Biomedical Advanced Research and Development Authority [HHSO100201300009C], which had a contract with the sponsor to perform the pediatric trials.

  • https://dx.doi.org/10.1124/dmd.120.000318.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (9)
Drug Metabolism and Disposition
Vol. 49, Issue 9
1 Sep 2021
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Research ArticleArticle

Using PBPK Modeling to Predict Pediatric CYP3A-Mediated DDIs

Sara N. Salerno, Fernando O. Carreño, Andrea N. Edginton, Michael Cohen-Wolkowiez and Daniel Gonzalez
Drug Metabolism and Disposition September 1, 2021, 49 (9) 844-855; DOI: https://doi.org/10.1124/dmd.120.000318

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Research ArticleArticle

Using PBPK Modeling to Predict Pediatric CYP3A-Mediated DDIs

Sara N. Salerno, Fernando O. Carreño, Andrea N. Edginton, Michael Cohen-Wolkowiez and Daniel Gonzalez
Drug Metabolism and Disposition September 1, 2021, 49 (9) 844-855; DOI: https://doi.org/10.1124/dmd.120.000318
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