Variations in pharmacokinetic-pharmacodynamic target values across MICs and their potential impact on determination of susceptibility test interpretive criteria.

BACKGROUND: An antibacterial drug's susceptibility test interpretive criteria (STIC) are determined by integrating clinical, microbiological and pharmacokinetic-pharmacodynamic (PK-PD) data. PTA analysis plays a pivotal or supportive role in STIC determination and is heavily dependent on the PK-PD target values determined from animal PK-PD studies. Therefore, variations in PK-PD target values may impact STIC determination. Factors contributing to variation in the PK-PD target values include the number of and MICs for bacterial isolates used in animal PK-PD studies. OBJECTIVES: To analyse the relationship between PK-PD target values and MICs, describe the variations in PK-PD target values of isolates and evaluate whether the proposed/target STICs were within the ranges of the MICs for isolates used in animal PK-PD studies. METHODS: A database was compiled for this research by screening animal PK-PD study reports submitted to the FDA from 10 new drug applications (NDAs). RESULTS: A relationship evaluation between PK-PD target values and MICs for tested isolates for seven drugs (that used AUC/MIC ratio as the PK-PD index) showed that, generally, the AUC/MIC values decreased with an increase in MIC. These target values were highly variable, with the percentage coefficient of variation ranging between 1% and 132% for isolates having the same MIC. For 16/27 (59%) drug/bacteria combinations from all 10 drugs, the proposed/target STICs were higher than the highest MIC for bacteria isolates evaluated, while 6/27 (22.5%) were lower. CONCLUSIONS: This research suggests that careful considerations related to selection of bacterial isolates for animal PK-PD studies could strengthen the STIC determination process.