2021 FDA Science Forum
Variations in Pharmacokinetic-Pharmacodynamic Target Values Across Minimum Inhibitory Concentrations and its Impact on Determination of Susceptibility Test Interpretive Criteria
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Background
Susceptibility Test Interpretive Criteria (STIC) are used in selecting an anti-bacterial treatment for a patient because they are considered to be correlated with clinical outcomes. Probability of Target Attainment (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 the STIC determination process. Factors contributing towards variation in the PK-PD target values include the number of bacterial isolates and range of minimum inhibitory concentrations (MICs) of isolates used in animal PK-PD studies. Purpose: To evaluate whether the proposed/target STICs were within the ranges of the MICs of isolates used in animal PK-PD studies, analyze the relationship between PK-PD target values and MICs, and describe the variations in PK-PD target values of isolates with the same MIC.
Methodology
A dataset of animal PK-PD studies was compiled from ten new drug applications (NDAs) submitted to the FDA and MIC value ranges of tested isolates were compared against the Applicant proposed STICs. Additional analyses were performed to evaluate variability in AUC/MIC values as well as their relationship with the MICs for tested isolates.
Results
In 16 (59%) of 27 drug/bacteria combinations, the proposed/target STICs were above the MIC range of bacteria isolates tested. The AUC/MIC values were highly variable with CV% ranging from 1% to 132 % for isolates having the same MIC and in general, an increase in MIC correlated with a decrease in AUC/MIC target values.
Conclusion
This research suggests that inadequate selection of isolates in animal PK-PD study may over- or under-estimate the STIC. While an underestimated STIC would increase the probability of favorable treatment outcome, it would also restrict treatment for some patients who may benefit from the treatment. In contrast, an overestimated STIC may increase the rates of treatment failure and antibiotic resistance development for a new antibiotic. To decrease these uncertainties rising from extrapolation, animal PK-PD studies could include a larger range of bacterial isolates with MICs up to and including the proposed STIC whenever possible.
