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

Xi-Wei Ji; Xiao Zhu; Yun Li; Feng Xue; Isabelle Hui San Kuan; Qing-Feng He; Xiang-Rui Meng; Xiao-Qiang Xiang; Yi-Min Cui; Bo Zheng

doi:10.3389/fphar.2022.856792

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

Front Pharmacol. 2022 Jul 18:13:856792. doi: 10.3389/fphar.2022.856792. eCollection 2022.

Authors

Xi-Wei Ji¹, Xiao Zhu², Yun Li¹, Feng Xue¹, Isabelle Hui San Kuan^{3

4}, Qing-Feng He², Xiang-Rui Meng⁵, Xiao-Qiang Xiang², Yi-Min Cui¹, Bo Zheng¹

Affiliations

¹ Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
² Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China.
³ Certara, Princeton, NJ, United States.
⁴ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
⁵ Intensive Care Unit, Xiyuan Hospital of China Academy of Traditional Chinese Medicine, Beijing, China.

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.