Gentamicin dosing strategies for dogs with subclinical renal dysfunction.

Twenty-six subtotally nephrectomized dogs were used as a model for subclinical renal dysfunction to evaluate the nephrotoxic potential of gentamicin administered according to four different dosage regimens. Dosages were individualized based on the pharmacokinetic disposition of drug in each dog. Gentamicin at 3.75 +/- 0.15 mg/kg (mean +/- standard error of the mean, total daily dose) was given for 12 days in two or three divided daily doses (BID and TID, respectively) or in a 2-h or 4-h once-daily variable-rate infusion (2HI and 4HI, respectively) with loading dose. Analyses of serum chemistries and pharmacokinetic data were performed on the ratio of pretreatment versus posttreatment parameters in individual animals. While serum chemistries and histopathology revealed no significant differences in toxicity between treatment groups, pharmacokinetic analysis revealed a significant difference in the ratio of pretreatment versus posttreatment gentamicin clearance (1.35 +/- 0.22, BID; 2.44 +/- 0.52, TID; 0.91 +/- 0.08, 2HI; 0.91 +/- 0.07, 4HI). By using mean population pharmacokinetic parameters (all dogs), predicted times for each treatment group administered 3.75 mg/kg per day to achieve concentrations in serum above the MICs of 2, 4, 6, and 8 micrograms/ml, respectively, were 7.8, 4.2, 2.0, and 0.6 (BID); 6.1, 3.0, 0.5, and 0.2 (TID); 7.1, 5.3, 4.2, and 3.5 (2HI); and 7.4, 5.8, 4.8, and 4.0 (4HI) h daily. This study suggests that decreasing the total daily dosage of drug may decrease the incidence of gentamicin-induced nephrotoxicity. Regardless of the dosage regimen, however, regimens may differ significantly in predicted therapeutic efficacy. Predicted 30-min postdosing concentrations in serum were lowest in dogs administered drug TID, and gentamicin clearance decreased in this group with treatment, suggesting that this regimen may be the least efficacious as well as the most prone to causing future nephrotoxicity.