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Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-3166-9981
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2018 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 24, no 7, p. 697-706Article, review/survey (Refereed) Published
Abstract [en]

Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.

Place, publisher, year, edition, pages
2018. Vol. 24, no 7, p. 697-706
Keywords [en]
Antibiotics, Drug combinations, Interaction, Semi-mechanistic pharmacokinetic-pharmacodynamic modelling, Simulations
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:uu:diva-366616DOI: 10.1016/j.cmi.2017.11.023ISI: 000436640800008PubMedID: 29229429OAI: oai:DiVA.org:uu-366616DiVA, id: diva2:1265897
Funder
Swedish Research Council, 2015-06826EU, FP7, Seventh Framework Programme, Health-F3-2011-278348Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved

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Brill, Margreke J. E.Kristoffersson, AndersZhao, ChenyanNielsen, Elisabet I.Friberg, Lena E

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