Pharmacokinetic-pharmacodynamic target attainment analysis of doripenem in infected patients

This study was a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of doripenem. Drug concentration data in plasma (115 samples) and urine (61 samples) from 18 infected patients were concurrently analysed to develop a more accurate population PK model for doripenem. In the final PK model, creatinine clearance (CL(Cr)) was the most significant covariate: C(Lr) (L/h) = 0.137 x CL(Cr); CL(nr) (L/h) = 2.49; V(1) (L) = 8.29; Q (L/h) = 8.10; and V(2) (L) = 9.37, where CL(r) and CL(nr) are the renal and non-renal clearances, V(1) and V(2) are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central-peripheral) clearance. Based on the PK model, a Monte Carlo simulation predicted the probabilities of attaining the bactericidal exposure target (40% of the time above the minimum inhibitory concentration (MIC)) in plasma and defined the PK-PD breakpoints (the highest MIC values at which the target attainment probabilities were >= 90%). The breakpoint for 500 mg every 8 h (q8h) (1-h infusion) with a CL(Cr) of 80 mL/min (1 mu g/mL) corresponded to those for 250 mg q8h with a CL(Cr) of 40 mL/min and 250 mg every 12 h with a CL(Cr) of 20 mL/min. Prolonging the infusion time was a more effective strategy than dose escalation to increase the breakpoint. These results provide guidance for constructing a PK-PD-based strategy for dosing guidance for tailoring doripenem regimens. (C) 2008 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.