Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, Hematology |
| Therapuetic Areas: | Hematology, Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | August 2010 |
| End Date: | February 2012 |
Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients With Possible Bacterial Infection
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))
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
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.
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