Pharmacokinetics of an Aminoglycoside in Hemodialysis Patients.

Overview

Aminoglycosides are widely used for the treatment of Gram-negative bacilli and Staphylococcus aureus infections because of their effectiveness and low cost. Nevertheless, many aspects of their optimal use in hemodialysis patients remain unsolved and little is known about their pharmacokinetics in this context. The current practice for prescribing aminoglycosides to these particular patients consists in giving after each hemodialysis session about half the dose usually given to patients with normal renal function. However, theoretical considerations and emerging clinical data suggest that this may not be the most beneficial dosing regimen as efficient peak concentrations are often not attained and the occurrence of ototoxicity and nephrotoxicity is still frequent.

Recent evidence about the pharmacokinetics and pharmacodynamics of aminoglycosides strongly supports administration of aminoglycosides before, rather than after, hemodialysis. Therapeutic drug monitoring using pharmacokinetic modeling is currently used in non-hemodialysis patients. However, the PK tools employed are not suitable to dialysis patients. For aminoglycosides, the ratio of peak to Minimal Inhibitory Concentration (MIC) has been shown to be the parameter that best correlates with clinical efficacy, whilst prolonged exposure to high concentrations have been related to either nephrotoxicity or ototoxicity. Additionally, aminoglycosides are mostly excreted as unchanged drugs in urine and their clearance is directly proportional to the glomerular filtration rate. The elimination half-life of aminoglycosides is approximately 1.5-3 hours in adults with normal renal function, but is greatly prolonged up to 36-70 hours in patients with end-stage renal failure. In a standard patient, aminoglycosides are administered as a single dose, over a short time interval, to obtain an elevated blood peak concentration (the effective level). The next injection is not administered before 24 hours, to allow the patient to wash out the aminoside and to minimize the residual blood concentration (the toxic level). The aim here is to maximize the peak concentration during a fair amount of time (by repeating the peaks) and to minimize the overall drug exposure, responsible for the toxicity. For the renal impaired patient, our hypothesis is that the hemodialyzer can be regarded as a kidney. Thus, the administration of the aminoside at the beginning of the hemodialysis could lead to profiles of elimination comparable to those observed in normorenal patients. The research aims at performing a population pharmacokinetic (POPPK) study of gentamicin when given to hemodialysis patients.