Population pharmacokinetic study of isepamicin with intensive care unit patients

Abstract

The pharmacokinetics (PK) of isepamicin, a new aminoglycoside, were studied in 85 intensive care unit (ICU) patients and were compared with those observed in 10 healthy volunteers. A parametric method based on a nonlinear mixed-effect model was used to assess population PK. Isepamicin was given intravenously over 0.5 h at dosages of 15 mg/kg once daily or 7.5 mg/kg twice daily. The data were fitted to a bicompartmental open model. Compared with healthy volunteers, the mean values of the PK parameters were profoundly modified in ICU patients: elimination clearance was reduced by 48%, the volume of distribution in the central compartment (Vc) was increased by 50%, the peripheral volume of distribution was 70% higher, the distribution clearance was 146% lower, and the elimination half-life was ca. 3.4 times higher. The interindividual variability in PK parameters was about 50% in ICU patients. Five covariates (body weight [BW], simplified acute physiology score [SAPS], temperature, serum creatinine level, and creatinine clearance [CLCR]) were tentatively correlated with PK parameters by multivariate linear regression analysis with stepwise addition and deletion. The variability of isepamicin clearance was explained by three covariates (BW, SAPS, and CLCR), that of Vc was explained by BW and SAPS, and that of the elimination half-life was explained by CLCR and SAPS. Simulation of the concentration-versus-time profile for 500 individuals showed that the mean peak (0.75 h) concentration was 18% lower in ICU patients than in healthy volunteers and that the range in ICU patients was very broad (28.4 to 95.4 mg/liter). Therefore, monitoring of the isepamicin concentration is in ICU patients is mandatory.

Comparison of two methods to obtain a desired first isepamicin peak in intensive care patients

“…those on mechanical ventilation and those with SAPS > 35, the percentages of patients reaching the desired value were significantly higher in the CD group. To calculate the initial dose for the CD strategy, we used a specific ICU population model [13], which was implemented in the PKS program. This specific ICU population was derived from the study by Tod et al.…”

“…In 12 patients, the peak concentration values exceeded 130 mg/L; such peaks are not optimal and are potentially nephrotoxic and ototoxic. According to the study by Tod et al [13], three covariates (body weight, CL CR and SAPS) contribute to the explanation of the variability in pharmacokinetic parameter values. In the PKS program (Abbott Diagnostics), SAPS is not implemented and is not considered for the calculation of the dose.…”

“…The dispersion of the population parameters used in the estimation process are given in and are derived from the study by Tod et al. [13].…”

“…CL T is described by the following equation: CL T CL NR + (CL slope´C L CR ), where CL NR is nonrenal clearance and CL slope is rate of change in drug clearance with respect to CL CR estimated with Cockroft and Gault. The dispersion of the population parameters used in the estimation process are given in Table I and are derived from the study by Tod et al [13].…”

“…Indeed, several specific patient variables influence aminoglycoside elimination and thereby affect serum concentrations; these include renal function, age, fever, catabolism, total serum proteins and modification of cardiac outpout. Thus, it is not surprising that wide interpatient variation of ISP concentrations have been observed in ICU patients [13]. Optimization of aminoglycoside doses and schedules to enhance therapeutic outcomes was recently reported [14,15].…”