Model-Informed Drug Development of New Cefoperazone Sodium and Sulbactam Sodium Combination (3:1): Pharmacokinetic/Pharmacodynamic Analysis and Antibacterial Efficacy Against Enterobacteriaceae

Abstract

Objective: Cefoperazone/sulbactam is a commonly used antibiotic combination against the extended-spectrum beta-lactamases (ESBLs)-producing bacteria. The objective of this study was to evaluate the efficacy of a new cefoperazone/sulbactam combination (3:1) for Enterobacteriaceae infection via model-informed drug development (MIDD) approaches. Methods: Sulperazon [cefoperazone/sulbactam (2:1)] was used as a control. Pharmacokinetic (PK) data was collected from a clinical phase I trial. Minimum inhibitory concentrations (MICs) were determined using two-fold broth microdilution method. The percent time that the free drug concentration exceeded the minimum inhibitory concentration (%fT_>MIC) was used as the pharmacokinetic/pharmacodynamic indicator correlated with efficacy. Models were developed to characterize the PK profile of cefoperazone and sulbactam. Monte Carlo simulations were employed to determine the investigational regimens of cefoperazone/sulbactam (3:1) for the treatment of infections caused by Enterobacteriaceae based on the probability of target attainment (PTA) against the tested bacteria. Results: Two 2-compartment models were developed to describe the PK profiles of cefoperazone and sulbactam. Simulation results following the single-dose showed that the regimens of cefoperazone/sulbactam combinations in the ratios of 3:1 and 2:1 achieved similar PTA against the tested bacteria. Simulation results from the multiple-dose showed that the dosing regimen of cefoperazone/sulbactam (4 g, TID, 3 g:1 g) showed slightly better antibacterial effect than cefoperazone/sulbactam (6 g, BID, 4 g:2 g) against the Escherichia coli (ESBL^-) and Klebsiella pneumoniae (ESBL^-). For the other tested bacteria, the above regimens achieved a similar PTA. Conclusions: Cefoperazone/sulbactam (3:1) showed similar bactericidal activity to sulperazon [cefoperazone/sulbactam (2:1)] against the tested bacteria. For the ESBL-producing and cefoperazone-resistant E. coli and K. pneumoniae, Cefoperazone/sulbactam (3:1) did not exhibit advantage as anticipated. Our study indicated that further clinical trials should be carried out cautiously to avoid the potential risks of not achieving the expected target.

Keywords: ESBLs; Monte Carlo simulation; PK/PD analysis; cefoperazone/sulbactam; enterobacteriaceae; model-informed drug development.

FIGURE 1

The goodness-of-fit plots of cefoperazone Pop-PK model. (A) Relationship between observed versus IPRED of PK; (B) Relationship between observed versus PRED of PK; (C) CWRES at different PRED; (D) CWRES at different time points. CWRES: conditional weighted residuals; PRED: predicted value; IPRED: individual predicted value. The thin solid lines represent the x = y lines. The thick solid lines are the trend lines.

FIGURE 2

The goodness-of-fit plots of sulbactam Pop-PK model. (A) Relationship between observed versus IPRED of PK; (B) Relationship between observed versus PRED of PK; (C) CWRES at different PRED; (D) CWRES at different time points. CWRES: conditional weighted residuals; PRED: predicted value; IPRED: individual predicted value. The thin solid lines represent the x = y lines. The thick solid lines are the trend lines.

FIGURE 3

Visual predictive check (VPC) of cefoperazone PK model (left: in logarithmic scale; right: in arithmetic scale). The range between the dashed lines depicts the 90th percentile intervals. The solid lines represent the medians of simulated data. Circles represent the observed data.

FIGURE 4

Visual predictive check (VPC) of sulbactam PK model (left: in logarithmic scale; right: in arithmetic scale). The range between the dashed lines depicts the 90th percentile intervals. The solid lines represent the medians of simulated data. Circles represent the observed data.