Population pharmacokinetics of gentamicin in haemodialysis patients: modelling, simulations and recommendations.

Abstract

The usual recommended dose for gentamicin is 3 to 7mg/kg/day for patients with a normal renal function while 1.7mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations. In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10mg/kg/day, with an inter-dose period of 24, 48 or 96h to predict the probability of having both a serum peak > 8*MIC and a trough < 1mg/L for MIC values between 0.25 and 4mg/L. A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2mg/kg/day (for MIC = 1mg/L) or 8mg/kg/day (for MIC = 4mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1mg/L at 96h for 92% and 34% respectively. The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3-8mg/kg/day just before dialysis, taking into account the type of infection.