Avibactam Pharmacokinetic/Pharmacodynamic Targets

Avibactam is a novel non-beta-lactam beta-lactamase inhibitor that has been approved in the United States and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for beta-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different in vitro and in vivo models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil. The PD driver of avibactam critical for restoring the activity of all three partner beta-lactams was found to be time dependent rather than concentration dependent and was defined as the time that the concentration of avibactam exceeded a critical concentration threshold (% fT>C-T). The magnitude of the CT and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner beta-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its beta-lactam partners.