Benapenem is a novel
carbapenem. The objective of this study was to determine the pharmacokinetic (PK)/pharmacodynamic (PD) cutoff values and evaluate the optimal administration regimens of
benapenem for the treatment of
bacterial infections via PK/PD modeling and simulation.
Ertapenem was used as a control. Infected mice received an intravenous (i.v.) injection of
benapenem or
ertapenem of 14.6, 58.4, or 233.6 mg/kg of
body weight, and the PK/PD profiles were evaluated. The MICs were determined by using a 2-fold
agar dilution method. Mathematical models were developed to characterize the pharmacokinetic profile of
benapenem in humans and mice. Monte Carlo simulations were employed to determine the cutoff values and the appropriate
benapenem dosing regimens for the treatment of
infections caused by clinical isolates of Enterobacteriaceae Two 2-compartment models were developed to describe the PK profiles of
benapenem in humans and mice. A two-site binding model was applied to fit the protein binding in mouse plasma. Through correlation analysis, the percentage of the time that the free drug concentration remains above the MIC (%fT>MIC) was determined to be the
indicator of efficacy. Results from the simulation showed that the probability of target attainment (PTA) against the tested isolates was over 90% with the dosing regimens studied. The PK/PD cutoff value of
benapenem was 1 mg/liter at a %fT>MIC of 60% when given at a dose of 1,000 mg/day by i.v. drip for 0.5 h. The established model provides a better understanding of the pharmacological properties of
benapenem for the treatment of
Enterobacteriaceae infections. The proposed PK/PD cutoff value suggests that
benapenem is a promising antibacterial against the Enterobacteriaceae The cutoff value of 1 mg/liter may be a useful guide for the clinical use of
benapenem and for surveillance for
benapenem resistance.