title: Clinical pharmacokinetics of meropenem and biapenem in bile and dosing considerations for biliary tract infections based on site-specific pharmacodynamic target attainment.
abstract: The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥ 90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥ 90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.
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: Akira
authors.initials: A
authors.lastname: Nakashima
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
authors.forename: Kayo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohge
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.forename: Taijiro
authors.initials: T
authors.lastname: Sueda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001659:Biliary Tract / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem; C065257:biapenem