POPULATION PHARMACOKINETICS OF GENTAMICIN IN PATIENTS WITH CANCER

Aims The purpose of this study was to describe the population pharmaco kinetics of gentamicin in patients with cancer, to identify possible r elationships between clinical covariates and population pharmacokineti c parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients . Methods Data were collected prospectively from 210 patients with can cer and were analysed with package NONMEM. Data were split into two se ts: a population data set and an evaluation set. Creatinine clearance was estimated using measured creatinine concentrations and using 'low' creatinines set to a minimum of 60 mu mol l(-1), 70 mu mol l(-1) or 8 8.4 mu mol l(-1). Results A two compartment model was fitted to the co ncentration-time curve. Two best models were obtained, one that relate d clearance to estimated creatinine clearance (minimum creatinine valu e 60 mu mol l(-1)) and the other that related clearance to age, creati nine concentration and body surface area. Volume of the central compar tment was influenced by body surface area and albumin concentration. F or both models 90% of measured concentrations lay within the 95% confi dence interval of the simulated concentrations and the mean prediction errors were -7.2% and -6.6%, respectively. A final analysis performed in all patients identified the following relationship CL. (1 h(-1)) = 0.88 x (1 + 0.043 x creatinine clearance) and central Volume of distr ibution V-1 (1) = 8.59 x body surface area x (albumin/34)(-0.39). The mean population estimate of intercompartmental clearance (Q) was 1.30 1 h(-1) and peripheral volume of distribution (V-2) was 9.80 l. Coeffi cient of variation was 18.5% on clearance and 28.2% on Q. Residual err or expressed as a standard deviation was 0.36 mg l(-1) at 1.0 mg l(-1) and 1.32 mg l(-1) at 8.0 mg l(-1). The mean population estimate of cl earance was 4.2 1 h(-1) and volume of distribution (V-ss) was 24.61 (0 .38 1 kg(-1)). The mean population estimates of half-lives were 1.8 h and 8.0 h. Conclusions In the context of published nomograms this anal ysis indicated that both the traditional approach and the new, 'once d aily' approach should achieve satisfactory concentrations in cancer pa tients although serum concentration monitoring is required to confirm optimal dosing in individual patients.