Analyses supporting phase 2 clinical trial dose selection for zabofloxacin in community-acquired pneumonia

Abstract number: P1261

Ambrose P., Bhavnani S., Jones R., Wikler M.

Objective: To conduct analyses in support of dose selection for zabofloxacin in Phase 2 community acquired pneumonia (CAP) studies. Phase 2 clinical trials will be initiated for zabofloxacin, a new antimicrobial agent belonging to the fluoroquinolone class. Zabofloxacin has high in vitro activity against pathogens associated with CAP/respiratory tract infections, including penicillin- and levofloxacin-non susceptible strains of Streptococcus pneumoniae.

Methods: Monte Carlo simulation (5,000 iterations) using Phase 1 pharmacokinetic (PK), protein binding, and non-clinical PK-PD data were utilised to determine the probability of attaining free-drug AUC:MIC target thresholds for daily doses of zabofloxacin ranging from 50 to 800 mg. PK data were derived from a randomised, placebo-controlled, ascending multiple-dose (dose range 200–800 mg daily orally for 7 days) study in 24 healthy volunteers. Zabofloxacin clearance (CL/F) was linear over the dose range studied, with a mean (SD) of 36.3 (12.8) L/hour. A point estimate of zabofloxacin binding to serum proteins of 77%, as estimated by ultra-filtration methodology, was used in the simulations. Free-drug AUC:MIC was calculated as the product of f, where f is the fraction unbound, and dose/CL/F. A log normal distribution for CL/F was assumed. Resultant free-drug AUC values were divided by fixed clinically relevant MIC values for zabofloxacin against pneumococci ranging from 0.008 to 0.25 mg/L (MIC50/90/99 for zabofloxacin against S. pneumoniae: 0.015/0.03/0.06 mg/L). The free-drug AUC:MIC target threshold evaluated in these analyses was 30, which was associated with complete eradication of S. pneumoniae from the lungs of immuno-competent mice (inoculated with 106 CFU) after treatment with zabofloxacin.

Results: The probabilities of PK-PD target attainment are presented in the Table.

Note that for daily doses of 300 mg or greater, the probability of PK-PD target attainment approaches 1.0 for MIC values as high as 0.03 mg/L, the MIC90 for zabofloxacin against S. pneumoniae.

Conclusion: These analyses support a 300 mg (or greater) once-daily dose-regimen for zabofloxacin for the treatment of CAP associated with S. pneumoniae.