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Physiologically Based Pharmacokinetic Prediction of Linezolid and Emtricitabine in Neonates and Infants

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Abstract

Introduction

Modeling and simulation approaches are increasingly being utilized in pediatric drug development. Physiologically based pharmacokinetic (PBPK) modeling offers an enhanced ability to predict age-related changes in pharmacokinetics in the pediatric population.

Methods

In the current study, adult PBPK models were developed for the renally excreted drugs linezolid and emtricitabine. PBPK models were then utilized to predict pharmacokinetics in pediatric patients for various age groups from the oldest to the youngest patients in a stepwise approach.

Results

Pharmacokinetic predictions for these two drugs in the pediatric population, including infants and neonates, were within a twofold range of clinical observations. Based on this study, linezolid and emtricitabine pediatric PBPK models incorporating the ontogeny in renal maturation describe the pharmacokinetic differences between adult and pediatric populations, even though the contribution of renal clearance to the total clearance of two drugs was very different (30 % for linezolid vs. 86 % for emtricitabine).

Conclusion

These results suggest that PBPK modeling may provide one option to help predict the pharmacokinetics of renally excreted drugs in neonates and infants.

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Acknowledgments

We thank Dr. Gerri Baer, Office of Pediatric Therapeutics, US FDA, for her critical review of the manuscript.

Author information

Authors and Affiliations

  1. Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA

    Peng Duan

  2. National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR, 72079, USA

    Jeffrey W. Fisher

  3. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Building 51, Rm 2154, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA

    Kenta Yoshida, Lei Zhang, Gilbert J. Burckart & Jian Wang

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  1. Peng Duan
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  2. Jeffrey W. Fisher
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  3. Kenta Yoshida
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  4. Lei Zhang
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  5. Gilbert J. Burckart
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  6. Jian Wang
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Corresponding author

Correspondence to Jian Wang.

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Funding

No external funding was used for this work or the preparation of the manuscript.

Disclosure

Dr Kenta Yoshida was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration (FDA).

Conflict of interest

Peng Duan, Jeffery W. Fisher, Kenta Yoshida, Lei Zhang, Gilbert J. Burckart, and Jian Wang have no conflicts of interest that are directly relevant to the content of this manuscript.

Disclaimer

The contents of this manuscript reflect the views of the authors and should not be interpreted as representing the US FDA’s views or policies. No official support or endorsement by the FDA is intended or should be inferred. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the FDA.

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Duan, P., Fisher, J.W., Yoshida, K. et al. Physiologically Based Pharmacokinetic Prediction of Linezolid and Emtricitabine in Neonates and Infants. Clin Pharmacokinet 56, 383–394 (2017). https://doi.org/10.1007/s40262-016-0445-9

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  • DOI: https://doi.org/10.1007/s40262-016-0445-9

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