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Review ArticleReview Article

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

Elisabet I. Nielsen and Lena E. Friberg
Dan Andersson, ASSOCIATE EDITOR
Pharmacological Reviews July 2013, 65 (3) 1053-1090; DOI: https://doi.org/10.1124/pr.111.005769
Elisabet I. Nielsen
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Lena E. Friberg
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Dan Andersson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Roles: ASSOCIATE EDITOR
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Abstract

Pharmacokinetic-pharmacodynamic (PKPD) modeling and simulation has evolved as an important tool for rational drug development and drug use, where developed models characterize both the typical trends in the data and quantify the variability in relationships between dose, concentration, and desired effects and side effects. In parallel, rapid emergence of antibiotic-resistant bacteria imposes new challenges on modern health care. Models that can characterize bacterial growth, bacterial killing by antibiotics and immune system, and selection of resistance can provide valuable information on the interactions between antibiotics, bacteria, and host. Simulations from developed models allow for outcome predictions of untested scenarios, improved study designs, and optimized dosing regimens. Today, much quantitative information on antibiotic PKPD is thrown away by summarizing data into variables with limited possibilities for extrapolation to different dosing regimens and study populations. In vitro studies allow for flexible study designs and valuable information on time courses of antibiotic drug action. Such experiments have formed the basis for development of a variety of PKPD models that primarily differ in how antibiotic drug exposure induces amplification of resistant bacteria. The models have shown promise for efficacy predictions in patients, but few PKPD models describe time courses of antibiotic drug effects in animals and patients. We promote more extensive use of modeling and simulation to speed up development of new antibiotics and promising antibiotic drug combinations. This review summarizes the value of PKPD modeling and provides an overview of the characteristics of available PKPD models of antibiotics based on in vitro, animal, and patient data.

Footnotes

  • This work was funded by the Swedish Foundation for Strategic Research and the Drug Disease Model Resources (DDMoRe) consortium, which is an Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115156, resources of which are composed of a financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions. The DDMoRe project is also supported by a financial contribution from academic and small and medium enterprises (SME) partners. This work does not necessarily represent the views of all DDMoRe partners.

  • dx.doi.org/10.1124/pr.111.005769

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 65 (3)
Pharmacological Reviews
Vol. 65, Issue 3
1 Jul 2013
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Review ArticleReview Article

PKPD-Modeling of Antibiotics

Elisabet I. Nielsen and Lena E. Friberg
Pharmacological Reviews July 1, 2013, 65 (3) 1053-1090; DOI: https://doi.org/10.1124/pr.111.005769

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Review ArticleReview Article

PKPD-Modeling of Antibiotics

Elisabet I. Nielsen and Lena E. Friberg
Pharmacological Reviews July 1, 2013, 65 (3) 1053-1090; DOI: https://doi.org/10.1124/pr.111.005769
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  • Article
    • Abstract
    • I. Introduction
    • II. Pharmacokinetics, Pharmacokinetics-Pharmacodynamics, and Drug Development
    • III. Pharmacokinetics-Pharmacodynamics of Antibiotics
    • IV. Pharmacokinetic-Pharmacodynamic Modeling of In Vitro Data
    • V. Pharmacokinetic-Pharmacodynamic Modeling of Animal Data
    • VI. Clinical Pharmacokinetics-Pharmacodynamics
    • VII. Some Practical Aspects of Pharmacokinetic-Pharmacodynamic Modeling
    • VIII. Future Perspectives
    • IX. Conclusions and Standpoints
    • Authorship Contributions
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