PHARMACOKINETICS AND PHARMACODYNAMICS OF MUREPAVADIN IN NEUTROPENIC MICE MODELS [Experimental Therapeutics]

Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein targeting antibiotics. It specifically interacts with LptD and inhibits LPS transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa. We determined the plasma protein binding, the pharmacokinetics of murepavadin in plasma and ELF (pulmonary) in infected animals as well as determining the exposure response relationship. Treatment of CD-1® neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24h, and the number of CFU per lung was determined. The maximum effect model was used to fit the dose-response and the Pharmacodynamic: index (PDI)-response to determine the PDI values resulting in a static and 1-log kill. Using R² as an indicator of the best fit, the fAUC/MIC correlated best with efficacy. The mean AUC required to provide a static effect was 36.83 mg.h/L (fAUC = 8.25 mg.h/L) and to provide a 1-log reduction was 44.0 mg.h/L (fAUC = 9.86 mg.h/L). The mean static fAUC/MIC was determined to be 27.78 and that for a 1-log reduction was 39.85. These data may serve to determine doses in humans that are likely to be efficacious.

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