title: 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 (CL(Cr)) was the most significant covariate: CL(r) (L/h)=0.137xCL(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 >or=90%). The breakpoint for 500 mg every 8h (q8h) (1-h infusion) with a CL(Cr) of 80 mL/min (1 microg/mL) corresponded to those for 250 mg q8h with a CL(Cr) of 40 mL/min and 250 mg every 12h 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.
authors.affiliation: Department of Clinical Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. ikawak@hiroshima-u.ac.jp
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Uehara
authors.forename: Koichi
authors.initials: K
authors.lastname: Monden
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Honda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003198:Computer Simulation; D000077726:Doripenem; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D010949:Plasma / Q000737:chemistry; D013997:Time Factors; D014556:Urine / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem