Population pharmacokinetics of gentamicin in patients with cancer

Gentamicin is an aminoglycoside antibiotic that is active against gram-negative aerobic bacilli and is standard therapy in the prophylaxis and treatment of gram-negative infections [1]. Febrile neutropenic patients are at risk of developing overwhelming septicaemia if not treated appropriately and aminoglycosides in combination with beta-lactam antibiotics are the standard empirical therapy in many centres [1]. There is evidence that the efficacy of aminoglycosides in patients with gram-negative bacteriaemia is influenced by the early achievement of a high peak to MIC ratio [2]. Increased aminoglycoside volume of distribution and clearance have been reported in adult patients with several types of solid and haematological malignancies. Manny & Huston [3]) found a distribution volume for all aminoglycosides of 0.41 (0.13 l kg−1 ) while Higa & Murray [4] identified a volume of distribution 1.14 times and clearance 1.63 times higher in cancer patients compared with the rest of the population. More recently, Inciardi et al. [5] performed a population pharmacokinetic study of gentamicin in cancer patients using a nonparametric expectaction maximization (NPEM) algorithm and estimated volume of distribution to be 0.30 l kg−1. Similar results were found by Ordores et al. [6]. Bertino et al. [7] compared the pharmacokinetics of gentamicin in 235 patients with malignancies with 645 patients with no malignancies and they found no differences in volume or clearance. Although both recent chemotherapy and neutropenia have been proposed as explanations for these observations, the reason for the apparent increase in volume is not known. Creatinine clearance is commonly used as an indicator of renal function and since gentamicin is eliminated almost exclusively by glomerular filtration, creatinine clearance estimates are often employed to determine initial doses of gentamicin. There are several methods of estimating creatinine clearance of which the most widely used is the Cockcroft-Gault equation [8]. This equation was derived from 249 male patients with stable renal function and it relates creatinine clearance to age, weight, sex and creatinine concentration. The factor for females was arbitrarily chosen. However, there are limitations to the value of creatinine concentration as a measure of glomerular filtration rate. Creatinine is produced as a byproduct of muscle metabolism [9] and its formation can be affected by several disease states and factors such as diet, exercise, age, and low muscle mass. Under these circumstances clearance of creatinine estimated from measured creatinine concentrations is a poor indicator of renal function [10, 11]. The correction of the measured creatinine concentration to a minimum of 88.4 μmol l−1 (1 mg dl−1 ) has been proposed by some investigators [11, 12] while others have found that 60 μmol l−1 is a useful cut-off [13]. The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer. In addition, since several factors have been shown to influence the pharmacokinetics of gentamicin, the aim was to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates. Finally, this study examines the relevance of existing dosage nomograms in light of the population model developed in these patients.