Document Detail

Pharmacodynamic variability beyond that explained by MICs.
MedLine Citation:
PMID:  23357773     Owner:  NLM     Status:  MEDLINE    
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 pharmacokinetic (PK) parameters and MICs, consideration of interstrain pharmacodynamic (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 percentage of the dosing interval for which free-drug concentrations exceed the MIC of the targeted strain (%fT>MIC) was calculated. Doripenem PD was excellently described with Hill-type models (r(2) > 0.98); significant differences between mean PD estimates determined using a two-stage approach versus population analyses were not observed (P > 0.05); however, the variance in 50% effective concentration (EC50) and maximum effect (Emax) among strains was much greater using the two-stage approach. Even using the population approach, interstrain variability in EC50 (coefficient of variation expressed as a percentage [CV%] = 29.2%) and H (CV% = 46.1%) parameters was substantive, while the variability in Emax (CV% = 19.7%) was modest. This resulted in extensive variability in the range of %fT>MIC targets associated with stasis to those associated with a 2-log10 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.
Rachel L Soon; Neang S Ly; Gauri Rao; Lance Wollenberg; Kuo Yang; Brian Tsuji; Alan Forrest
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Publication Detail:
Type:  Journal Article     Date:  2013-01-28
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  57     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-09-06     Revised Date:  2013-10-08    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1730-5     Citation Subset:  IM    
State University of New York at Buffalo School of Pharmacy and Pharmaceutical Science, Buffalo, New York, USA.
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MeSH Terms
Anti-Bacterial Agents / pharmacokinetics*,  pharmacology,  therapeutic use
Bacteria / drug effects
Carbapenems / pharmacokinetics*,  pharmacology,  therapeutic use
Microbial Sensitivity Tests / methods*
Monte Carlo Method
Thigh / microbiology
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Carbapenems; 0/doripenem

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