A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam.
Int J Infect Dis
; 89: 55-61, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-31479762
ABSTRACT
OBJECTIVES:
Relebactam is a small molecule ß-lactamase inhibitor under clinical investigation for use as a fixed-dose combination with imipenem/cilastatin. Here we present a translational pharmacokinetic/pharmacodynamic mathematical model to support optimal dose selection of relebactam.METHODS:
Data derived from in vitro checkerboard and hollow fiber infection studies of imipenem-resistant strains of Pseudomonas aeruginosa were incorporated into the model. The model integrates the effect of relebactam concentration on imipenem susceptibility in a semi-mechanistic manner using the checkerboard data and characterizes the bacterial time-kill profiles from the hollow fiber infection model data.RESULTS:
Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC=7.5 associated with 2-log kill. At a clinical dose of 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4µg/mL.CONCLUSIONS:
The study confirms that the pharmacokinetic/pharmacodynamic driver for relebactam is fAUC/MIC, that an fAUC/MIC ratio of 7.5 is associated with 2-log kill in vitro, and that a 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pseudomonas aeruginosa
/
Infecções por Pseudomonas
/
Imipenem
/
Compostos Azabicíclicos
/
Inibidores de beta-Lactamases
/
Antibacterianos
/
Modelos Teóricos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article