Population Pharmacokinetic Analysis of Piperacillin/Tazobactam in Korean Patients with Acute Infections

Abstract

Background: For more effective and safer usage of antibiotics, the dosing strategy should be individualized based on the patients' characteristics, including race. The aim of this study was to investigate the population pharmacokinetic (PK) profiles of piperacillin and tazobactam in Korean patients with acute infections.

Materials and methods: At least four consecutive 2/0.25 g or 4/0.5 g doses of piperacillin/tazobactam (TZP) were intravenously infused over 1 h every 8 h for patients with creatinine clearance (CL(cr)) ≤50 ml/min or CL(cr) >50 mL/min, respectively. Blood samples from 33 patients at a steady-state were taken pre-dose and at 0 min, 30 min, and 4-6 h after the fourth infusion. The population PK analysis was conducted using a non-linear mixed-effects method. A likelihood ratio test was used to select significant covariates, with significance levels of P < 0.05 for selection and P < 0.01 for elimination.

Results: Both piperacillin PK and tazobactam PK were well described by a two-compartment model with first-order elimination. Creatinine clearance and body weight, as covariates on clearance (CL) and volume of central compartment (V1), were selected among the covariates possibly affecting PK parameters of both drugs. CL was defined as CL = 2.9 + 4.03 × CL(cr) /47 for piperacillin and CL = 1.76 + 4.81 × CL(cr) /47 for tazobactam. V1 was defined as V1 = 19.5 × weight/60 for piperacillin and V1 = 22.6 × weight/60 for tazobactam.

Conclusion: The PK profiles of TZP at a steady-state in Korean patients with acute infections were well described by a two-compartment model with first-order elimination. Both piperacillin and tazobactam clearances were significantly influenced by creatinine clearance.

Keywords: Clearance; Piperacillin; Population pharmacokinetics; Race; Tazobactam.

Figure 1

Goodness of fit plots for the final pharmacokinetic models for piperacillin (4 figures of the upper panel) and tazobactam (4 figures of the lower panel). The grey line indicates the line of identity; the red line indicates the linear regression line. CWRES: conditional weighted residual.

Figure 2

Visual predictive check for the final piperacillin pharmacokinetic model, simulation of 2,000 data sets, using the final pharmacokinetic parameter estimates. Open circles indicate observed concentrations; the red full line indicates the median value; the lower and upper red dotted lines indicate the 2.5^th and 97.5^th predicted value, respectively.