POPULATION PHARMACOKINETIC STUDY OF AMIKACIN ADMINISTERED ONCE OR TWICE-DAILY TO FEBRILE, SEVERELY NEUTROPENIC ADULTS

Once daily (o.d.) administration of 20 mg of amikacin per kg of body w eight 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 deter mine in neutropenic patients (i) the influence of the dosing regimen o n 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 c haracteristics on the disposition of amikacin and (iv) to provide a ra tionale for dosing recommendations, we evaluated the population pharma cokinetics of amikacin administered to 57 febrile neutropenic adults ( neutrophil count, <500/mm(3)) being treated for a hematological disord er 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 b lood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels wer e measured by the enzyme-multiplied immunoassay technique. A mixed-eff ect modeling approach was used to fit a bicompartmental model to the d ata (NONMEM software). The influences of the dosing regimen and the de mographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the po pulation model. The dosing regimen had no influence on amikacin pharma cokinetic 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, s ex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distri bution, the distribution clearance, and the tissue volume of distribut ion were 15, 30, and 25%, respectively. On the basis of the expected d istribution of amikacin concentrations in this population, dosing reco mmendations as a function of creatinine clearance (CLCR) are proposed: for patients with normal renal function (CLCR of 80 to 130 ml/min), 2 0 mg/kg o.d. is recommended, whereas for patients with severe renal im pairment (CLCR, 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is r ecommended.