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Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gary E. Stein, Pharm.D., Michigan State University
ClinicalTrials.gov Identifier:
NCT01401010
First received: July 14, 2011
Last updated: May 2, 2012
Last verified: May 2012
History of Changes
  Purpose

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))


Condition Intervention Phase
Febrile Neutropenia
 Drug: Doripenem
Drug: doripenem
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients With Possible Bacterial Infection

Resource links provided by NLM:

Drug Information available for: Doripenem
U.S. FDA Resources

Further study details as provided by Michigan State University:

Primary Outcome Measures:
  • Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients [ Time Frame: 1, 4, 6, 8 hours after at least two doses of drug ] [ Designated as safety issue: No ]
    To determine the serum pharmacokinetic volume of distribution of doripenem in febrile neutropenic patients with pneumonia. We obtained blood at 1, 4, 6, 8 hours after at least two doses of doripenem and measured these levels (mg/L)by HPLC assay.

  • Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients [ Time Frame: 1, 4, 6, 8 hours after at least two doses of drug ] [ Designated as safety issue: No ]
    To determine the serum pharmacokinetic elimination rate constant of doripenem in febrile neutropenic patients with pneumonia. We obtained blood at 1, 4, 6, 8 hours after at least two doses of doripenem and measured these levels (mg/L)by HPLC assay.

  • Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients [ Time Frame: 1, 4, 6, 8 hours after at least two doses of drug ] [ Designated as safety issue: No ]
    To determine the serum pharmacokinetic half life of doripenem in febrile neutropenic patients with pneumonia. We obtained blood at 1, 4, 6, 8 hours after at least two doses of doripenem and measured these levels (mg/L)by HPLC assay.

  • Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients [ Time Frame: 1, 4, 6, 8 hours after at least two doses of drug ] [ Designated as safety issue: No ]
    To determine the serum pharmacokinetic clearance of drug of doripenem in febrile neutropenic patients with pneumonia. We obtained blood at 1, 4, 6, 8 hours after at least two doses of doripenem and measured these levels (mg/L)by HPLC assay.

  • Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients [ Time Frame: 1, 4, 6, 8 hours after at least two doses of drug ] [ Designated as safety issue: No ]
    To determine the serum pharmacokinetic area under serum curve of doripenem in febrile neutropenic patients with pneumonia. We obtained blood at 1, 4, 6, 8 hours after at least two doses of doripenem and measured these levels (mg/L)by HPLC assay.


Secondary Outcome Measures:
  • Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) [ Time Frame: 1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters ] [ Designated as safety issue: No ]

    Following determination of pharmacokinetic (PK) parameters from patients with febrile neutropenia, Monte Carlo simulations were then conducted to determine time of serum concentrations above the MIC (40% of the time) against Gram-negative isolates.

    These Gram-negative isolates had a range of minimum inhibitory concentrations (MIC) to Doripenem.



Enrollment: 12
Study Start Date: August 2010
Study Completion Date: February 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Doripenem 500 mg
pharmacokinetics/pharmacodynamics
 Drug: Doripenem
500 mg every 8 hours
Other Name: Doribac
Active Comparator: Doripenem 1000 mg
pharmacokinetics/pharmacodynamics
 Drug: doripenem
1000 mg every 8 hours
Other Name: Doribac

Detailed Description:

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01401010

Locations
United States, Michigan
Sparrow Hospital
Lansing, Michigan, United States, 48910
Sponsors and Collaborators
Gary E. Stein, Pharm.D.
Investigators
Principal Investigator: Gary Stein, PharmD Michigan State University
  More Information

No publications provided

Responsible Party: Gary E. Stein, Pharm.D., Professor of Medicine and Pharmacology, Michigan State University
ClinicalTrials.gov Identifier: NCT01401010     History of Changes
Other Study ID Numbers: DORIBAC4006a
Study First Received: July 14, 2011
Results First Received: March 6, 2012
Last Updated: May 2, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Michigan State University:
neutropenia
doripenem

Additional relevant MeSH terms:
Bacterial Infections
Fever
Neutropenia
Body Temperature Changes
Signs and Symptoms
 Agranulocytosis
Leukopenia
Leukocyte Disorders
Hematologic Diseases

ClinicalTrials.gov processed this record on May 22, 2013