Pharmacokinetic–pharmacodynamic target attainment analysis of doripenem in infected patients

Abstract: 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 (CLCr) was the most significant covariate: CLr (L/h)=0.137×CLCr; CLnr (L/h)=2.49; V 1 (L)=8.29; Q (L/h)=8.10; and V 2 (L)=9.37, where CLr and CLnr 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 500mg every 8h (q8h) (1-h infusion) with a CLCr of 80mL/min (1μg/mL) corresponded to those for 250mg q8h with a CLCr of 40mL/min and 250mg every 12h with a CLCr of 20mL/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. [Copyright &y& Elsevier]