title: Optimal dosing regimen of biapenem in Chinese patients with lower respiratory tract infections based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation.
abstract: In this study, a population pharmacokinetic (PPK) model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs) was developed and optimal dosage regimens based on Monte Carlo simulation were proposed. A total of 297 plasma samples from 124 Chinese patients were assayed chromatographically in a prospective, single-centre, open-label study, and pharmacokinetic parameters were analysed using NONMEN. Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance. The final PPK model was: CL (L/h)=9.89+(CLCr-66.56)×0.049; Vc (L)=13; Q (L/h)=8.74; and Vp (L)=4.09. Monte Carlo simulation indicated that for a target of ≥40% T>MIC (duration that the plasma level exceeds the causative pathogen's MIC), the biapenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was 4μg/mL for doses of 0.3g every 6h (3-h infusion) and 1.2g (24-h continuous infusion). For a target of ≥80% T>MIC, the PK/PD breakpoint was 4μg/mL for a dose of 1.2g (24-h continuous infusion). The probability of target attainment (PTA) could not achieve ≥90% at the usual biapenem dosage regimen (0.3g every 12h, 0.5-h infusion) when the MIC of the pathogenic bacteria was 4μg/mL, which most likely resulted in unsatisfactory clinical outcomes in Chinese patients with LRTIs. Higher doses and longer infusion time would be appropriate for empirical therapy. When the patient's symptoms indicated a strong suspicion of Pseudomonas aeruginosa or Acinetobacter baumannii infection, it may be more appropriate for combination therapy with other antibacterial agents.
authors.affiliation: Department of Pharmacy, Gongli Hospital of Pudong New Area in Shanghai, Shanghai, China; Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: Tongji University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yuancheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine, Gongli Hospital of Pudong New Area in Shanghai, Shanghai, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, Gongli Hospital of Pudong New Area in Shanghai, Shanghai, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Gongli Hospital of Pudong New Area in Shanghai, Shanghai, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China. Electronic address: chenxj-lab@hotmail.com.
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002681:China; D004359:Drug Therapy, Combination; D016972:Enterobacter cloacae / Q000187:drug effects / Q000302:isolation & purification; D013293:Enterococcus faecalis / Q000187:drug effects / Q000302:isolation & purification; D016984:Enterococcus faecium / Q000187:drug effects / Q000302:isolation & purification; D004926:Escherichia coli / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011446:Prospective Studies; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology*; D013210:Staphylococcus / Q000187:drug effects / Q000302:isolation & purification; D013845:Thienamycins / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; C065257:biapenem
keywords: %T(>MIC); Biapenem; Lower respiratory tract infections; Monte Carlo simulation; Population pharmacokinetics