title: Pharmacodynamic evaluation of biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation.
abstract: This study evaluated the pharmacodynamics of biapenem in peritoneal fluid (PF). Biapenem (300 or 600mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CL(Cr)) as the most significant covariate: CL (L/h)=0.036 x CL(Cr)+4.88, V1 (L)=6.95, Q2 (L/h)=2.05, V2 (L)=3.47, Q3 (L/h)=13.7 and V3 (L)=5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration (T>MIC)) in PF were greater than or equal to those in plasma. In the cases of CL(Cr)=90 and 60mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were >or=90%) were 2microg/mL for 300mg every 12h, 4microg/mL for biapenem 300mg every 8h (q8h) and 8microg/mL for 600mg q8h. Thus, these results should support the clinical use of biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.
authors.affiliation: Department of Clinical Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, 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: Kayo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohge
authors.forename: Taijiro
authors.initials: T
authors.lastname: Sueda
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001202:Ascitic Fluid / Q000378:metabolism* / Q000382:microbiology; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D006801:Humans; D007813:Laparotomy; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D013530:Surgical Wound Infection / Q000188:drug therapy / Q000382:microbiology; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; C065257:biapenem