Population pharmacokinetic study of amikacin administered once or twice daily to febrile, severely neutropenic adults

Abstract

Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm3) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL[CR]) are proposed: for patients with normal renal function (CL[CR] of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL[CR], 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.

FIG. 1

Simulation of amikacin kinetics for a typical patient (CL_CR = 100 ml/min) using a one- or two-compartment model.

FIG. 2

Scatter plot of predicted versus observed amikacin concentrations. Predicted concentrations were calculated by using the population model, the covariates of each patient, and the patient’s dosing history.

FIG. 3

Weighted residuals (i.e., the difference between the observed and the predicted concentrations normalized to their SDs) versus time. Each points represents one observation.

FIG. 4

Scatter plot of amikacin clearance versus estimated CL_CR. Amikacin clearance was estimated by the Bayesian method. CL_CR was estimated as described by Cockcroft and Gault (8).

FIG. 5

Simulation of amikacin kinetics at steady state for male and female patients following administration of a 20-mg/kg dose. The middle pair of curves is the mean profile based on data for 500 fictitious individuals. The upper and lower pairs of curves are ±2 SD around the mean. For each pair of curves, the upper curve is for females and the lower curve is for males.