| Pharmacodynamic variability beyond that explained by minimum inhibitory concentrations (MICs). | |
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MedLine Citation:
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PMID: 23357773 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Monte-carlo simulations (MCS) present a powerful tool to evaluate candidate regimens by determining the probability of target attainment. Although these assessments have traditionally incorporated variability in PK parameters and MICs, consideration of inter-strain PD variability has been neglected. A population PK/PD model was developed for doripenem using murine-thigh infection data based on 20 bacterial strains. PK data were fit to a linear two-compartment model with first-order input and elimination processes and an absorption lag-time from a separate site (r(2)>0.96). PK parameters were utilized to simulate free drug profiles for various regimens in PD studies, from which the %fT>MIC was calculated. Doripenem PD was excellently described with Hill-type models (r(2)>0.98); significant differences were not observed between mean PD estimates determined using a two-stage versus population analyses (p>0.05), however the variance in EC(50) and E(max) amongst strains was much greater using the two-stage approach. Even using the population approach, interstrain variability in EC(50) (CV%=29.2) and H (CV%=46.1) parameters was substantive, while the variability in E(max) (CV%=19.7) was modest. This resulted in extensive variability in the range of %fT>MIC targets associated with stasis to 2-log(10)-reduction in bacterial burden (CV%∼50%). It appears that MCS, based on the assumption that PD variability is due to MIC alone underestimates variability, and may consequently underestimate treatment failures. |
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Authors:
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Rachel L Soon; Neang Ly; Gauri Rao; Lance Wollenberg; Kuo Yang; Brian Tsuji; Alan Forrest |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-28 |
Journal Detail:
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Title: Antimicrobial agents and chemotherapy Volume: - ISSN: 1098-6596 ISO Abbreviation: Antimicrob. Agents Chemother. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0315061 Medline TA: Antimicrob Agents Chemother Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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State University of New York at Buffalo School of Pharmacy and Pharmaceutical Science, Buffalo, New York. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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