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 ( Arbekacin [1-N-(S)-4-amino-2-hydroxybutyl dibekacin] is an effective aminoglycoside antibiotic against methicillin-resistant Staphylococcus aureus (MRSA) and is stable in the presence of aminoglycoside-inactivating enzymes produced by MRSA (1,10,22). Arbekacin is a derivative of dideoxykanamycin B (dibekacin), developed in Japan, with specific activities against both gram-positive and gram-negative bacteria (16). The anti-MRSA potency of arbekacin was superior to that of vancomycin (1), and arbekacin showed a longer postantibiotic effect than vancomycin did (44).In this decade, arbekacin, vancomycin, and teicoplanin have been used for the treatment of MRSA infections in Japan. Similar to other aminoglycosides, arbekacin is excreted exclusively in urine in its unchanged form via glomerular filtration, and some portion is reabsorbed by tubular reabsorption. In subjects with normal renal function receiving a single intramuscular dose of 3 mg/kg of body weight (typical half-life of arbekacin is 1.5 to 2.7 h), the apparent volume of distribution (V) is 0.28 to 0.37 liter/kg, and the total body clearance (CL) is 97 to 146 ml/min per 1.73 m 2 (6). In patients with severe renal insufficiency (creatinine clearance [CL CR ], Ͻ10 ml/min), the half-life is 18.5 to 46.4 h, the apparent V is 0.26 to 0.56 liter/kg, and total body CL is 8 to 12 ml/min per 1.73 m 2 (6). Thus, linear relationships are observed between arbekacin pharmacokinetics and the glomerular filtration rate.Although the approved dose and dosage of arbekacin for adult patients (150 to 200 mg per day) is usually administered as a divided dose by intravenous or intramuscular injection, therapeutic drug monitoring (TDM) is often used to achieve drug concentrations within the therapeutic range for individual patients. Since patients treated with arbekacin usually suffer from severe infections, it is important to reach the target therapeutic concentration quickly. The effective peak concentration of arbekacin is presumed to be 7 to 12 g/ml, and the safe trough concentration is less than 2 g/ml. However, these recommended serum concentrations of arbekacin were based on other aminoglycosides, such as gentamicin, amikacin, and...

The efficacy and safety of high-dose arbekacin sulfate therapy (once-daily treatment) in patients with MRSA infection

“…The results suggest that it may also be necessary to lower the standard trough drug level a little more, but the recommended level could not be determined from the relationship between the presence or absence of adverse reactions and the blood drug levels in the present study (t test: trough level, P = 0.1368; peak level, P = 0.1898). In addition, it is necessary to extend the dose interval when renal function is compromised [14]. The dose interval was set at 36 h in one patient and 48 h in five patients, and five of the six patients showed response to the drug.…”

Pharmacokinetic-Pharmacodynamic Relationship of Arbekacin for Treatment of Patients Infected with Methicillin-Resistant Staphylococcus aureus

“…Clinical data were obtained from a noninterventional observational study performed at 51 institutions, members of The Anti-MRSA Drug TDM Study Group (see Acknowledgments) from 1999 through 2002 (21). The serum drug concentration data of hospitalized patients treated with arbekacin for a suspected MRSA infection were collected as routine therapeutic drug monitoring data.…”

“…Complete details on the population pharmacokinetic modeling and results for arbekacin are described in the companion article (21). Briefly, arbekacin pharmacokinetics was described using a two-compartment model with elimination of the central compartment.…”

Population pharmacokinetics of arbekacin in different infectious disease settings and evaluation of dosing regimens

“…Moreover, the dose-dependent adverse effects are closely related to the trough concentration (Ctrough > 2 mg/mL) of the drug [2]. The population pharmacokinetics of arbekacin in Japanese patients, concentration-response relationships of arbekacin, and optimal concentration targets of arbekacin for efficacy and safety have been previously reported [2,13]. However, further population pharmacokinetic analyses have been necessary to better estimate the population pharmacokinetic parameters in order to accurately predict the pharmacokinetic parameters for each patient infected with various disease types, such as bacteremia and pneumonia.…”

“…Further studies have been necessary to investigate the changes in the pharmacokinetics during the hypermetabolic phase, such as physiological changes. Clinical pharmacokinetic studies of arbekacin evaluating changes in patients with different types of infections have been limited by a small number of trials, small sample sizes, varying populations and methodological differences [13,14].…”