Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man

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Abstract
The pathogenesis of aminoglycoside nephrotoxicity is directly related to the accumulation of drug within the renal cortex. To identify measures that might prevent aminoglycoside nephrotoxicity, we investigated the influence of various dosage regimens on the renal cortical accumulation of amikacin and tobramycin in man. Patients undergoing nephrectomy for a renal tumour with normal renal function and no proteinuria received (i) a single dose of either amikacin (15 mg/kg) or tobramycin (4·5 mg/kg) given iv over 30 min, or (ii) a 24-h continuous infusion of either drug or (iii) amikacin as two injections of 7·5 mg/kg or tobramycin as three injections of 1·5 mg/kg over the 24 h preceding nephrectomy. Serum aminoglycoside pharmacokinetics were examined and renal cortical tissue was sampled for drug determination at operation. A single injection yielded cortical concentrations of 115·4±21·8 and 68·9±30·3 mg/kg for amikacin and tobramycin, respectively. Tissue levels after continuous infusion were 171·7±42·9 and 100·0±30·0 mg/kg for amikacin and tobramycin, respectively. Two injections of 7·5 mg/kg amikacin resulted in renal cortical concentrations of 196·9 ± 54·9 and three injections of 1·5 mg/kg tobramycin resulted in renal cortical concentration of 76·5 ± 18 mg/kg. The AUC for the three dosage regimens was not significantly different for the two aminoglycosides indicating linear serum pharmacokinetics for these drugs. In the case of amikacin, a single injection resulted in significantly lower drug levels than did a continuous infusion or administration of the same dose over three injections. In contrast the administration of 4·5 mg/kg of tobramycin as single injection, continuous infusion or as three injections of 1·5 mg/kg resulted in renal concentrations which were not statistically significantly different. From the point of view of nephrotoxicity, these data support the administration of amikacin as a single daily injection. Further studies to determine the clinical efficacy of once-daily dosing for amikacin appear justified.

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