Pharmacodynamics of NOSO-502 studied in vitro and in vivo: determination of the dominant pharmacodynamic index driver

Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class - the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver. Methods: A dilutional pharmacokinetic system was used for in vitro experiments. In vivo experiments were conducted in the neutropenic murine thigh infection model. Three Escherichia coli and two Klebsiella pneumoniae strains were used. NOSO-502 pharmacokinetics (PK) in mice were described in a population PK model. Dose fractionation and escalation exposures were performed and bacteriostatic and 1log₁₀ and 2log₁₀ kill effects were determined using an E_max model. The coefficient of determination (R²) was used to estimate the variance that might be due to regression with various PDIs (fAUC/MIC, fC_max/MIC, %fT_>MIC and fAUC/MIC per length of dosing interval fAUC/MIC·1/tau). Results: Exposure fractionation in both in vitro and in vivo studies indicated that 6-hourly dosing resulted in a greater reduction in K. pneumoniae bacterial burden compared with either 12- or 24-hourly dosing. Similar observations were made with three E. coli strains in vitro and a single strain of E. coli in vivo. For K. pneumoniae, R² for fAUC/MIC·1/tau was 0.8376 in vitro and 0.6001 in vivo, which was greater than R² with other PDIs. Analysis of pooled in vitro data from three strains of E. coli produced an R² of 0.7073 for fAUC/MIC and 0.6100 for fAUC/MIC·1/tau. Conclusions: NOSO-502 exhibits both dose- and time-dependent in vitro and in vivo activity against both E. coli and K. pneumoniae.