Pharmacokinetics and monte carlo simulations of doripenem in patients with febrile neutropenia

• Published in: The Annals of pharmacotherapy Vol. 46; no. 10; p. 1281
• Main Authors: Stein, Gary E, Kulhanek, Grace, Smith, Curtis L, Kuti, Joseph L, Nicolau, David P, Scharmen, Amy, Farnum, Chris, Tran, MaryAnn, Kalra, Apoorv, Havlichek, Daniel H
• Format: Journal Article
• Language: English
• Published: United States 01.10.2012
• Subjects: Adult; Aged; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Carbapenems - administration & dosage; Carbapenems - blood; Carbapenems - pharmacokinetics; Female; Gram-Negative Bacteria - drug effects; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Neutropenia - drug therapy; Neutropenia - metabolism; Young Adult
• ISSN: 1542-6270
• DOI: 10.1345/aph.1R097

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. 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. 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)). 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. 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.