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A pharmacokinetic-pharmacodynamic (PKPD) model based on in vitro time-kill data predicts the in vivo PK/PD index of colistin.
- Source :
-
The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2016 Jul; Vol. 71 (7), pp. 1881-4. Date of Electronic Publication: 2016 Mar 16. - Publication Year :
- 2016
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Abstract
- Objectives: For antibiotics, extensive animal PKPD studies are often performed to evaluate the PK/PD driver for subsequent use when recommending dosing regimens. The aim of this work was to evaluate a PKPD model, developed based on in vitro time-kill data for colistin, in predicting the relationships between PK/PD indices and the bacterial killing previously observed in mice.<br />Methods: An in silico PKPD model for Pseudomonas aeruginosa exposed to colistin was previously developed based on static in vitro time-kill data. The model was here applied to perform an in silico replication of an in vivo study where the effect of colistin on P. aeruginosa was studied in the thigh infection model. Concentration-time profiles of unbound colistin were predicted and used as input to drive the bacterial killing in the PKPD model. The predicted bacterial count at 24 h was related to each of the PK/PD indices and the results were compared with reported observations in vivo.<br />Results: The model was found to adequately predict in vivo results from mice; both in terms of which PK/PD index best correlates to effect (fAUC/MIC) as well as the magnitude needed for a 2 log kill. The fAUC/MIC needed to achieve a 2 log reduction in bacterial counts after 24 h was here predicted to be 9 compared with 31 previously reported in vivo.<br />Conclusions: This study provides further support that PKPD models based on longitudinal data can be a useful tool to make drug development more efficient within the infectious diseases area.<br /> (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
Anti-Bacterial Agents administration & dosage
Colistin administration & dosage
Computer Simulation
Disease Models, Animal
Mice
Microbial Sensitivity Tests
Microbial Viability drug effects
Pseudomonas Infections drug therapy
Pseudomonas Infections microbiology
Time Factors
Anti-Bacterial Agents pharmacokinetics
Anti-Bacterial Agents pharmacology
Colistin pharmacokinetics
Colistin pharmacology
Pseudomonas aeruginosa drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2091
- Volume :
- 71
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of antimicrobial chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 26983860
- Full Text :
- https://doi.org/10.1093/jac/dkw057