Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

Febrile Neutropenia Clinical Trial

Official title:

Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients With Possible Bacterial Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01401010
• Other study ID #: DORIBAC4006a
• Status: Completed
• Phase: Phase 4
• First received: July 14, 2011
• Last updated: October 12, 2015
• Start date: August 2010
• Est. completion date: February 2012

Study information

• Verified date: October 2015
• Source: Michigan State University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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))

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: February 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Febrile Neutropenia
• Fever
• Neutropenia

Intervention

Drug:
• Doripenem
500 mg every 8 hours
• doripenem
1000 mg every 8 hours

Locations

Country	Name	City	State
United States	Sparrow Hospital	Lansing	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Gary E. Stein, Pharm.D.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients	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.	1, 4, 6, 8 hours after at least two doses of drug	No
Primary	Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients	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.	1, 4, 6, 8 hours after at least two doses of drug	No
Primary	Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients	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.	1, 4, 6, 8 hours after at least two doses of drug	No
Primary	Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients	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.	1, 4, 6, 8 hours after at least two doses of drug	No
Primary	Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients	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.	1, 4, 6, 8 hours after at least two doses of drug	No
Secondary	Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC))	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.	1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters	No