title: Pharmacokinetic–pharmacodynamic target attainment analysis of meropenem in Japanese adult patients.
abstract: This study was a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of meropenem in Japanese adult patients. Plasma drug concentration data (265 samples from 42 patients) were used for population PK modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (40% of the time above the MIC for the bacterium). The final population PK model identified creatinine clearance (Cl(cr), ml/min) and body weight (BW, kg) as the most significant covariates: Cl (l/h) = 0.0905 × Cl(cr) + 2.03, V(c)(l) = 0.199 9 BW, Q (l/h) = 4.02, and V(p) (l) = 4.55, where Cl is the clearance, Vc and Vp are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the intercompartmental clearance. The Monte Carlo simulation developed the PK-PD breakpoints (the highest MIC values at which the probabilities of target attainment in plasma are 80% or more) for meropenem regimens, the values of which varied with the Cl(cr) and BW of the patient. The simulation also demonstrated that 0.25 g every 12 h (0.5-h infusion) achieved a target attainment probability of 82.4-100% against Escherichia coli, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae isolates. However, against Pseudomonas aeruginosa isolates, 0.5 g every 8 h or 1 g every 8 h was required to achieve 80% or more probability in most typical patients. These results provide a PK-PD-based strategy for tailoring a meropenem regimen according to Clcr and BW of a Japanese adult patient and susceptibility of the causative bacteria.
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: Hiroki
authors.initials: H
authors.lastname: Ohge
authors.forename: Kayo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Taijiro
authors.initials: T
authors.lastname: Sueda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kurisu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006095:Gram-Positive Cocci / Q000187:drug effects*; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests / Q000592:standards; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem