Bicompartmental kinetics of tobramycin analysed with a wide range of covariates.

ABSTRACT

The pharmacokinetics of tobramycin was studied in adult patients (N = 151) admitted either for initial suspicion of Gram-negative infection or for prophylaxis. In addition to age, weight, height and creatinine clearance (CrCL), a range of other covariates were also analysed, including type of pathology, co-medication, fever, sex and ethnicity (Basque or not). All patients received 100mg tobramycin every 8 h and samples were collected at three time points after the first dose and at two time points after the fourth dose and assayed with a fluorescence polarisation immunoassay. The population mixed effects bicompartmental parameters were obtained from 725 concentration measurements using NONMEM, FOCE method, and were systemic clearance, CL = 6.03 L/h (between-subject coefficient of variation (CV) %, 29.4%); volume of distribution, V = 15.04 L (7.3%); and intercompartmental constants, k(12) = 0.192 h(-1) (56%) and k(21) = 0.55 h(-1) (no CV% determined). Covariate modelling was performed within NONMEM. Two alternative significant covariate models (Models 1 and 2) are proposed, with functions of CrCL and/or sex (Model 2). However, for clinical purposes, differentiation by sex is insignificant. Model 1 is for CL = 3.1 + 0.05.CrCLL/h (17.3%); V = 14.6 L (12%); k(12) = 0.224 h(-1) (63%) and k(21) = 0.468 h(-1). Stochastic simulation was used to predict the expected concentration 95th percentiles after the recommended 7 mg/kg dose and for minimum inhibitory concentration (MIC) = 1 mg/L, as well as alternative once-daily dosing regimens for MIC = 2 mg/L. It is seen that once-daily high-dose tobramycin is an appropriate strategy with respect to pharmacodynamic indices, C(peak)/MIC or AUC/MIC (where C(peak) is the peak plasma concentration and AUC is the area under the concentration-time curve).