Aminoglycoside Dosages and Nephrotoxicity
- 187 Downloads
To develop a model that relates the probability of occurrence of nephrotoxicity to the cumulative area under the curve (AUC) of amikacin serum concentration.
Design and patients
This was a retrospective study of two groups of patients in whom nephrotoxicity was observed after administration of amikacin. The first group consisted of patients treated with once-daily administration (ODA) [n = 13]. The second group consisted of patients treated with twice-daily administration (TDA) [n = 22].
Main outcome measure
The probability of nephrotoxicity occurrence.
The model is a powerful tool to represent and describe the influence of the dosage regimen on aminoglycoside nephrotoxicity. The onset of nephrotoxicity is delayed in the ODA group (p = 0.01) for the same total daily dose among the two groups. The cumulative serum AUC values at onset of nephrotoxicity were greater for the ODA group (p = 0.029). In addition, for the same probability of nephrotoxicity occurrence (50%), the cumulative AUC for the ODA dosage regimen is 2 613 mg · h/L versus only 1 521 mg · h/L for the TDA dosage regimen. The difference in nephrotoxicity between ODA and TDA is greatest for a cumulative AUC of 2 495 mg · h/L, which corresponds to standard therapy with amikacin 900 mg/day during a 7-day period, i.e. 15 mg/kg/day for a 60kg patient with normal renal function (initial creatinine clearance >80 mL/min). For an AUC above 2 495 mg · h/L, the difference in nephrotoxicity decreases slowly to zero. This result means that ODA is especially justified when the treatment is administered over a short duration, i.e. less than 7 days.
The utility of selecting ODA in order to obtain less nephrotoxicity in comparison with TDA is therefore not established when the treatment is prolonged. In clinical use, the choice of the dosage regimen is not clear-cut, and both expected efficacy and expected toxicity must be taken into account in order to obtain an overall optimisation of each patient’s therapy.
KeywordsDosage Regimen Amikacin Renal Cortex Serum Creatinine Concentration Tubuloglomerular Feedback
This study was funded by Hospices Civils de Lyon, without any grant from Bristol-Myers Squibb; however ADCAPT was funded by this company several years ago.
- 1.Maire PH, Corvaisier S, Rougier F, et al. Pharmacocinétique/ pharmacodynamie clinique des antibiotiques. In: Freney J, Renaud F, Hansen W, Bollet C, editors. Précis de bactériologie clinique. Paris: Elsevier, 2000: 715–31Google Scholar
- 8.USC*PACK [computer program]. Version 10.7. Los Angeles, CA: Laboratory of Applied Pharmacokinetics, University of Southern California. School of Medicine; 1995. USC*PACK PC Collection Clinical Research ProgramsGoogle Scholar
- 10.Schumitzky A. Non-parametric EM algorithms for estimating prior distributions. Los Angeles: Laboratory of Applied Pharmacokinetics, University of Southern California, School of Medicine; 1990. Technical Report: 90-2Google Scholar
- 12.Jelliffe RW. The USC*PACK PC programs for population pharmacokinetic modeling of large kinetic/dynamic systems, and adaptive control of drug dosage regimens. Proc Annu Symp Comput Appl Med Care 1991, 922-4Google Scholar
- 13.Maurin M, Rougier F, Maire P. Note de calcul sur les lois de Hill: aspects probabiliste, déterministe et épistémologique 2000. Edition INRETS-LTE 2026. ISRN: INRETS/NST/00-548-FRGoogle Scholar
- 14.Hill AV. The possible effects of the aggregation of hemoglobin on its dissociation curve. J Physiol 1910; 40: iv–viiGoogle Scholar
- 15.Michaelis L, Menten ML. Die kinetik der Invertinwirkung. Biochem Z 1913; 49: 333–69Google Scholar
- 17.McCullagh P, Neider JA. Generalized linear models. London: Chapman and Hall, 1983Google Scholar
- 19.Guiliano RA, Verpooten GA, Verbist L, et al. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986; 236: 470–5Google Scholar
- 23.Schnermann J, Häberle DA, Davis JM, et al. Tubuloglomerular feedback control of renal vascular resistance. In: Windhager E, editor. Handbook of renal physiology. Oxford: Oxford University Press, 1992: 1675–705Google Scholar
- 26.Gonzales LS, Spencer JP. Aminoglycosides: a practical review. Am Fam Physician 1998; 58: 1811–20Google Scholar