Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients
Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients
Primary: To determine the serum pharmacokinetics (PK) of doripenem in febrile neutropenic
 patients.

 Secondary: Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported
 as Probability of Target Attainment (40% Time (fT)> minimum inhibitory concentration (MIC))
Background: Doripenem is a group 2 carbapenem with enhanced in vitro activity against
 Gram-negative bacteria including Pseudomonas aeruginosa. Currently, there is a paucity of
 pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia.

 Objectives: To conduct a pharmacokinetic and safety evaluation of two doses of doripenem in
 febrile neutropenic patients and provide probability estimates of attaining effective drug
 exposure against common Gram-negative pathogens.

 Methods: We obtained multiple blood samples from 12 adult patients with febrile neutropenia
 who were receiving either 500 mg or 1000 mg of doripenem IV 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 HPLC assay. The derived pharmacokinetic
 (PK) parameters from these serum levels were utilized to perform a 5000 patient Monte Carlo
 simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008 to 64 mg/L
 to determine probability estimates of time of free drug concentration > MIC (fT>MIC).

 Results: The mean PK parameters in these patients were a volume of distribution (Vd) of
 43.9L, an elimination rate constant (k) of 0.37 hr -1, a total clearance (Cl) of 14.4 L/h,
 and an area under the concentration-time curve (AUC) of 57.6 mg∙h/L. An optimal probability
 of target attainment (40% fT>MIC) of 90% was obtained against bacteria with MICs ≤ 2.0 and ≤
 4.0 mg/L with 500 mg and 1000 mg doses, respectively. Adverse events associated with
 doripenem were not observed in these patients.

 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. Pseudomonas aeruginosa) in patients with febrile neutropenia
Inclusion Criteria:

 -  adult neutropenic (< 500 cells) patients who are febrile

 Exclusion Criteria:

 -  Patients with Creatinine Clearance < 30 ml/min or allergy to carbapenems will be
 excluded.