title: Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data.
abstract: 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 (CL(Cr)) 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 CL(Cr) of 90 mL/min, prolongation of infusion time (from 0.5 h to 1.5 h) increased the PK-PD breakpoint from 1 μg/mL to 2 μg/mL with a 500 mg dose every 8h (q8h) and from 2 μg/mL to 4 μg/mL with a 500 mg dose every 6h (q6h). Meanwhile, in a patient with a CL(Cr) of 20 mL/min, the PK-PD breakpoints for both 0.5-h and 1.5-h infusions were 1 μg/mL with a 250 mg dose every 12h (q12h), 2 μg/mL with a 250 mg dose q8h and a 500 mg dose q12h, and 4 μg/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.
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.forename: Kayo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohge
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001424:Bacterial Infections / Q000150:complications* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D051437:Renal Insufficiency / Q000150:complications*; D013997:Time Factors; D014556:Urine / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D015378:Imipenem