Pharmacokinetic-pharmacodynamic target attainment analysis of doripenem in infected patients

摘要

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: CL_r (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 sim_ulation 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 high_est 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 p.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 infu_sion 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.