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 administer ed to 11 healthy volunteers in a randomized, crossover single-dose stu dy 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 fitte d to a two-compartment pharmacokinetic model, In addition, to mimic th e clinical setting, subjects' data were fitted by the Sawchuk-Zaske me thod, Distributional and postdistributional peak concentrations, along with the last obtained concentration in serum, were utilized to compa re the following pharmacokinetic variables: volume of distribution at steady state (V-ss), half-life, clearance (CL), and maximum concentrat ion in serum (C-max), With two-compartment pharmacokinetic fitting, si gnificant 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]) wer e found between traditional-dose and high-dose groups, respectively, W hen the data for concentrations in sera were fitted to a one-compartme nt pharmacokinetic model by using either the distributional or the pos tdistributional C-max, statistically significant differences (P less t han or equal to 0.001) were found between V-ss, half-life, CL, and C-m ax values for both dosage groups, The results show that the pharmacoki netics of gentamicin at a large dose differ significantly from those a t the traditional dose, This information has direct implications for o nce-daily aminoglycoside (ODA) literature when the C-max values report ed are distributional and therefore show falsely high C-max/MIC ratio estimates, In addition, ODA nomogram dosing tools developed with distr ibutional C-max values are probably inaccurate.