title: Pharmacokinetics and monte carlo simulations of doripenem in patients with febrile neutropenia.
abstract: BACKGROUND
  Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia.
  
  
  OBJECTIVE
  To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens.
  
  
  METHODS
  We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every 8 hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT(>MIC)).
  
  
  RESULTS
  The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h(-1), a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg•h/L. An optimal probability of target attainment (40% fT(>MIC)) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed.
  
  
  CONCLUSIONS
  The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.
authors.affiliation: Department of Medicine, Michigan State University, East Lansing, USA. Gary.Stein@hc.msu.edu
authors.forename: Gary E
authors.initials: GE
authors.lastname: Stein
authors.forename: Grace
authors.initials: G
authors.lastname: Kulhanek
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Smith
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: Amy
authors.initials: A
authors.lastname: Scharmen
authors.forename: Chris
authors.initials: C
authors.lastname: Farnum
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Tran
authors.forename: Apoorv
authors.initials: A
authors.lastname: Kalra
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Havlichek
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D015780:Carbapenems / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000077726:Doripenem; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D009503:Neutropenia / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem