Yiying Chen,1,2,* Bo Chen,1,2,* Yingbin Huang,1,2 Xueyong Li,1 Junnan Wu,1,2 Rongqi Lin,1– 3 Ming Chen,1,2 Maobai Liu,1 Hongqiang Qiu,1,2 Yu Cheng1,2 

1Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 2College of Pharmacy, Fujian Medical University, Fuzhou, 350004, People’s Republic of China; 3Shanghang County Hospital, Longyan, 364200, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hongqiang Qiu; Yu Cheng, Department of Pharmacy, Fujian Medical University Union Hospital, 29 Xin Quan Road, Fuzhou, Fujian, 350001, People’s Republic of China, Tel/Fax +86 591 86218591, Email hongqiangqiu@fjmu.edu.cn; chengyu@fjmu.edu.cn

Purpose: This study aimed to describe the population pharmacokinetics (PopPK) of ceftazidime-avibactam (CAZ-AVI) in adult patients, and to develop optimal dosing regimens for both non-critically ill and critically ill patients by combining different pharmacokinetic/pharmacodynamic (PK/PD) targets.
Patients and Methods: A prospective, single-center study involving patients who were infected with CRKP and received CAZ-AVI therapy was conducted. Nonlinear mixed-effect modeling was used to develop a PopPK model. The optimal dosing regimen was assessed using Monte Carlo simulation.
Results: The PopPK analysis of CAZ-AVI included 91 steady-state concentrations from 45 adult patients. The data were modeled using a one-compartment model. The typical population values of CAZ and AVI clearances were 2.96 L/h and 3.09 L/h, and the volumes of distribution were 17.76 L and 18.25 L, respectively. Our study showed that creatinine clearance (CrCL) calculated using the Cockcroft-Gault equation significantly affected the pharmacokinetics of CAZ-AVI. The Monte Carlo simulation optimized the dosing regimen for both non-critically ill and critically ill patients with varying renal functions, providing detailed supplements to the instructions.
Conclusion: Our study established a PopPK model for CAZ-AVI and proposed a reference for dosing regimen adjustment based on the severity of the disease and renal functional status.

Keywords: ceftazidime-avibactam, pharmacokinetic modeling, renal function, Monte Carlo simulation, dose optimization