Avibactam Pharmacokinetic/Pharmacodynamic Targets

Area of Science:

• Pharmacology
• Microbiology
• Infectious Diseases

Background:

• Avibactam is an approved non-β-lactam β-lactamase inhibitor used with ceftazidime.
• Avibactam combinations with aztreonam and ceftaroline fosamil are under clinical evaluation.
• Limited precedence exists for pharmacokinetic/pharmacodynamic (PK/PD) indices of β-lactamase inhibitors in population PK modeling.

Purpose of the Study:

• To identify the PK/PD index and exposure magnitude for avibactam in preclinical models.
• To determine avibactam's PK/PD target when combined with ceftazidime, aztreonam, or ceftaroline fosamil.

Main Methods:

• Preclinical *in vitro* and *in vivo* studies were conducted.
• PK/PD modeling was used to analyze avibactam exposure and effect.
• The critical PK/PD index was identified as %fT>CT (time above critical concentration threshold).

Main Results:

• Avibactam's efficacy is time-dependent, not concentration-dependent.
• The critical PK/PD target (%fT>CT) was identified for avibactam.
• The required threshold magnitude and duration varied based on the model and partner β-lactam.

Conclusions:

• Avibactam's PK/PD target is time-dependent (%fT>CT).
• Understanding this target is crucial for optimizing dosing and susceptibility breakpoints.
• Further research is needed to define precise targets for different avibactam combinations.