Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data

In this study, a pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis of imipenem (IPM) in patients with impaired renal function was conducted. IPM (500 mg) was administered via a 0.5-h or 1-h infusion to 27 patients with varying renal function. A population PK model was developed by simultaneously fitting plasma and urinary concentration data. A two-compartment model adequately described IPM pharmacokinetics, and creatinine clearance (CLCr) was identified as the most significant covariate. A PK-PD simulation predicted the probabilities of attaining the target in plasma [40% of the time above the minimum inhibitory concentration (MIC)] and defined the PK-PD breakpoints (the highest MICs at which the probabilities were >= 90%). In a patient with a CLCr of 90 mL/min, prolongation of infusion time (from 0.5 h to 1.5 h) increased the PK-PD breakpoint from 1 mu g/mL to 2 mu g/mL with a 500 mg dose every 8 h (q8h) and from 2 mu g/mL to 4 mu g/mL with a 500 mg dose every 6 h (q6h). Meanwhile, in a patient with a CLCr of 20 mL/min, the PK-PD breakpoints for both 0.5-h and 1.5-h infusions were 1 mu g/mL with a 250 mg dose every 12 h (q12h), 2 mu g/mL with a 250 mg dose q8h and a 500 mg dose q12h, and 4 mu g/mL with a 250 mg dose q6h. These results indicate that a shorter dosing interval is beneficial in patients with impaired renal function as it results in greater PK-PD breakpoints and a reduction in excessive maximum plasma concentrations. These results help to optimise IPM regimens, particularly in patients with impaired renal function. (C) 2012 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.