Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

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))

Study Overview

• Status: Completed
• Conditions: Febrile Neutropenia
• Intervention / Treatment: Drug: Doripenem; Drug: doripenem

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

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Sparrow Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Doripenem 500 mg; pharmacokinetics/pharmacodynamics	Drug: Doripenem; 500 mg every 8 hours; Other Names: Doribac
Active Comparator: Doripenem 1000 mg; pharmacokinetics/pharmacodynamics	Drug: doripenem; 1000 mg every 8 hours; Other Names: Doribac

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Gary E. Stein, Pharm.D.
• Investigators: Principal Investigator: Gary Stein, PharmD, Michigan State University

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: July 14, 2011
• First Submitted That Met QC Criteria: July 22, 2011
• First Posted (Estimate): July 25, 2011

Study Record Updates

• Last Update Posted (Estimate): October 14, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: neutropenia; doripenem
• Additional Relevant MeSH Terms: Wounds and Injuries; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Neutropenia; Hyperthermia; Fever; Febrile Neutropenia; Anti-Infective Agents; Anti-Bacterial Agents; Doripenem
• Other Study ID Numbers: DORIBAC4006a