Pharmacokinetics of gentamicin at traditional versus high doses: Implications for once-daily aminoglycoside dosing

Two doses of gentamicin (2 and 7 mg/kg of body weight) were administered to 11 healthy volunteers in a randomized, crossover single-dose study to compare their pharmacokinetics. Doses were infused over 1 h with a syringe infusion pump, and 14 concentrations in sera were obtained over an 8-h period, Concentration in serum versus time data were fitted to a two-compartment pharmacokinetic model, In addition, to mimic the clinical setting, subjects' data were fitted by the Sawchuk-Zaske method, Distributional and postdistributional peak concentrations, along with the last obtained concentration in serum, were utilized to compare the following pharmacokinetic variables: volume of distribution at steady state (V-ss), half-life, clearance (CL), and maximum concentration in serum (C-max), With two-compartment pharmacokinetic fitting, significant differences in distribution half-life (average, 21.8 and 41.6 min [P less than or equal to 0.05]) and gentamicin CL (76.6 +/- 6.6 and 67.2 +/- 4.2 ml/min/1.73 m(2) [P less than or equal to 0.001]) were found between traditional-dose and high-dose groups, respectively, When the data for concentrations in sera were fitted to a one-compartment pharmacokinetic model by using either the distributional or the postdistributional C-max, statistically significant differences (P less than or equal to 0.001) were found between V-ss, half-life, CL, and C-max values for both dosage groups, The results show that the pharmacokinetics of gentamicin at a large dose differ significantly from those at the traditional dose, This information has direct implications for once-daily aminoglycoside (ODA) literature when the C-max values reported are distributional and therefore show falsely high C-max/MIC ratio estimates, In addition, ODA nomogram dosing tools developed with distributional C-max values are probably inaccurate.