Paper Info
Title
A Novel Approach to Pharmacodynamic Assessment of Antimicrobial Agents: New Insights to Dosing Regimen Design.
Abstract
Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens) or time-dependent (for which more frequent dosing is preferred). While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e. g., agents which exhibit partial concentration-dependent killing). A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax) of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e. g., AUC/MIC, Cmax/MIC, %T>MIC) could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem). The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection.
Year
DOI
Venue
2011
10.1371/journal.pcbi.1001043
PLOS COMPUTATIONAL BIOLOGY
Keywords
Field
DocType
drug design,drug development,area under curve,spectrum,antimicrobial agent
Antimicrobial,Regimen,Biology,Drug development,Meropenem,Pharmacology,Moxifloxacin,Pharmacodynamics,Bioinformatics,Dosing,Cmax
Journal
Volume
Issue
ISSN
7
1
1553-7358
Citations 
PageRank 
References 
0
0.34
0
Authors
2
Name
Order
Citations
PageRank
Vincent H. S. Tam172.80
Michael Nikolaou2255.15