The magnitude of the pharmacodynamic index for NOSO-502: pathogen clearance, emergence of resistance and human dose predictions.

Abstract

BACKGROUND: NOSO-5O2 is the first clinical candidate of a new antimicrobial class, the odilorhabdins. The pharmacodynamics of NOSO-502 was studied to establish the magnitude of the pharmacodynamic index (PDI) and make human dose predictions. METHODS: In vitro experiments using different types of media were performed in time-kill curves and a pharmacokinetic model. In vivo experiments were conducted in the neutropenic murine thigh infection model. Six E. coli (MIC 1-8&#x2005;mg/L) and two K. pneumoniae (MIC 1-2&#x2005;mg/L) strains were used. 24&#x2005;h bacteriostatic and 1- and 2-log10 kill effects were related to fAUC0-24/MIC and fAUC0-24/MIC per length of dosing interval (fAUC0-24/MIC&#xb7;1/tau). Human pharmacokinetic parameters were predicted using interspecies allometric scaling and used to simulate the dose needed to reach the bacteriostatic PDI target for E. coli. RESULTS: The in vitro activity of NOSO-502 was dependent on the media and the strength of Mueller-Hinton Broth II (MHBII) used such that fAUC0-24/MIC ratios were higher when measured in 100% MHBII than 50% MHBII. In vivo for E. coli, the fAUC0-24/MIC for bacteriostatic effect and 1-log10 reduction in bacterial count were 10.7&#x200a;&#xb1;&#x200a;10.9 and 18.2&#x200a;&#xb1;&#x200a;16.5, respectively. The final human predicted parameters of the model had CV values of <20%. The human dose required to achieve the bacteriostatic fAUC0-24/MIC for each E. coli strain varied from 149 to 1717&#x2005;mg/day. CONCLUSIONS: A combination of the use of PDI targets and prediction of human pharmacokinetics allowed effective doses of NOSO-502 in man to be estimated.