Dosing of Gentamicin in Patients With End‐Stage Renal Disease Receiving Hemodialysis

Abstract

The aim of this study was to evaluate dosing schedules of gentamicin in patients with end-stage renal disease and receiving hemodialysis. Forty-six patients were recruited who received gentamicin while on hemodialysis. Each patient provided approximately 4 blood samples at various times before and after dialysis for analysis of plasma gentamicin concentrations. A population pharmacokinetic model was constructed using NONMEM (version 5). The clearance of gentamicin during dialysis was 4.69 L/h and between dialysis was 0.453 L/h. The clearance between dialysis was best described by residual creatinine clearance (as calculated using the Cockcroft and Gault equation), which probably reflects both lean mass and residual clearance mechanisms. Simulation from the final population model showed that predialysis dosing has a higher probability of achieving target maximum concentration (Cmax) concentrations (> 8 mg/L) within acceptable exposure limits (area under the concentration-time curve [AUC] values > 70 and < 120 mg x h/L per 24 hours) than postdialysis dosing.

Influence of Hemodialysis on Gentamicin Pharmacokinetics, Removal During Hemodialysis, and Recommended Dosing

“…Two of these regimens have been previously explored in an earlier publication (14,15), and one was found to be the most desirable for this type of dosing. We performed simulations, assuming a hemodialysis treatment scheme of 2 d-2 d-3 d intradialytic periods.…”

“…Recent data in hemodialysis patients receiving aminoglycosides suggest that extended interval aminoglycosides may be a reasonable dosing method if the drugs are administered just before hemodialysis (14,16). This allows high peak concentrations followed by removal by hemodialysis, minimizing sustained elevated serum concentrations.…”

“…The serum concentrations were simulated for one wk after the first gentamicin dose and included 3 doses of gentamicin and 3 dialysis sessions. At each peak (30 min after the end of the 30 min infusion), the percent of simulated patients who achieved a target of Ն8 g/ml, predose or predialysis or predose concentration Ͻ2 g/ml, AUC Ն140 g/h per ml and AUC Յ240 g/h per ml 48 h postdose (14,15). The final predialysis or predose concentration was obtained 164 h after the initial dose or 72 h after the third dose because of the nature of the hemodialysis scheduling.…”

“…Several studies have been performed evaluating gentamicin pharmacokinetics in patients with chronic kidney disease (2)(3)(4), and numerous others have evaluated gentamicin removal by "traditional" hemodialysis, (2,3,(5)(6)(7)(8)(9)(10)(11) newer dialytic techniques (12), and alternative dosing strategies (13)(14)(15)(16). The removal of gentamicin by the dialyzers studied is highly variable across these studies and is due in part to the different types of dialyzers used, length of dialysis sessions, hemodialysis operating characteristics, patient characteristics, delivered Kt/V, etc.…”

“…This is due to the difficulty in achieving high peak/MIC ratios while minimizing "trough" concentrations with conventional dosing regimens. A novel way to administer aminoglycosides to patients receiving hemodialysis, such that pharmacodynamics may be maximized, was described a decade ago (13) and more recently evaluated (14,15). These studies evaluated the potential for administering aminoglycosides immediately before hemodialysis, rather than after hemodialysis.…”