Population pharmacokinetics of Arbekacin in patients infected with methicillin-resistant Staphylococcus aureus

Abstract

Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CL(CR)), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CL(CR) + (26.5/age) (CL(CR) < 80 ml/min) and CL (liter/h) = 0.0130 CL(CR) + 0.0342WT + (26.5/age) (CL(CR) >/= 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

FIG. 1.

Profile of serum arbekacin concentration versus time. A total of 1,581 serum concentrations versus time for arbekacin following a single intravenous infusion of 15 min to 2 h in 403 subjects are plotted.

FIG. 2.

Estimated individual clearance of arbekacin versus creatinine clearance actually measured or estimated by the Cockroft-Gault method. The two lines represent the population mean described in the final model with a break at 80 ml/min of creatinine clearance.

FIG. 3.

Box and whisker plots showing V₁ values for healthy subjects (n = 50) and patients with infectious diseases classified by the type of illness, pneumonia or sepsis (n = 285), burn (n = 15), or other disease type (n = 53). V₁ values (liter/kilogram) calculated by the Bayesian method and 25, 50, and 75 percentiles, whiskers at ± 1.5 times the interquartile range, and outliers are denoted. The differences between healthy subjects and patients with various diseases were tested by the Dunnett test. The data were log transformed to approximate a normal distribution.

FIG. 4.

Scatter plots of predictions versus observed concentrations and weighted residual versus predictions.

FIG. 5.

Simulated serum arbekacin concentration profiles in different situations. (A) Comparison of data from a healthy subject and a patient with pneumonia with the same background and dosage regimen (100 mg/12 h). (B) Simulation curve of data for a pneumonia patient with a once-daily regimen (200 mg/24 h). (C) Simulation curve of data for a patient with pneumonia with renal impairment. The target peak concentration is not lower than 7 μg/ml (broken lines), and the trough concentration is lower than 2 μg/ml (dotted line).