Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

• Sponsor: Gary E. Stein, Pharm.D. (Other)
• Overall Status: Completed
• CT.gov ID: NCT01401010
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arms: 2
• Duration (Months): 18
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief 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))

Condition or Disease	Intervention/Treatment	Phase
Febrile Neutropenia	Drug: Doripenem; Drug: doripenem	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients With Possible Bacterial Infection
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients [1, 4, 6, 8 hours after at least two doses of drug]

   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.

2. Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients [1, 4, 6, 8 hours after at least two doses of drug]

   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.

3. Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients [1, 4, 6, 8 hours after at least two doses of drug]

   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.

4. Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients [1, 4, 6, 8 hours after at least two doses of drug]

   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.

5. Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients [1, 4, 6, 8 hours after at least two doses of drug]

   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

1. Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) [1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Sparrow Hospital	Lansing	Michigan	United States	48910

Sponsors and Collaborators

• Gary E. Stein, Pharm.D.

Investigators

• Principal Investigator: Gary Stein, PharmD, Michigan State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gary E. Stein, Pharm.D., Professor of Medicine and Pharmacology, Michigan State University
• ClinicalTrials.gov Identifier: NCT01401010
• Other Study ID Numbers: DORIBAC4006a
• First Posted: Jul 25, 2011
• Last Update Posted: Oct 14, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Gary E. Stein, Pharm.D., Professor of Medicine and Pharmacology, Michigan State University: neutropenia; doripenem
• Additional relevant MeSH terms: Neutropenia; Febrile Neutropenia; Hyperthermia; Fever; Doripenem

Study Results

Participant Flow

Recruitment Details	Subjects were inpatients (Sparrow Hospital) with febrile neutropenia who were treated with doripenem; referral base was infectious disease consultations. The first patient was enrolled 6-15-2010 and the last 8-21-2011.

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg
Arm/Group Description	pharmacokinetics/pharmacodynamics	pharmacokinetics/pharmacodynamics
Period Title: Overall Study
STARTED	6	6
COMPLETED	5	6
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg	Total
Arm/Group Description	pharmacokinetics/pharmacodynamics	pharmacokinetics/pharmacodynamics	Total of all reporting groups
Overall Participants	5	6	11
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 100%	5 83.3%	10 90.9%
>=65 years	0 0%	1 16.7%	1 9.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49 (17)	49 (18)	49 (17.5)
Sex: Female, Male (Count of Participants)
Female	3 60%	0 0%	3 27.3%
Male	2 40%	6 100%	8 72.7%
Region of Enrollment (participants) [Number]
United States	5 100%	6 100%	11 100%

Outcome Measures

1. Primary Outcome

Title	Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients
Description	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.
Time Frame	1, 4, 6, 8 hours after at least two doses of drug

Outcome Measure Data

Analysis Population Description

Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing.

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg	Combined Results for Both 500 and 1000 mg
Arm/Group Description	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results
Measure Participants	5	6	11
Mean (Standard Deviation) [Liters]	36.7 (15.9)	49.9 (18.1)	43.9 (17.7)

2. Secondary Outcome

Title	Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC))
Description	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.
Time Frame	1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters

Outcome Measure Data

Analysis Population Description

Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing.

Arm/Group Title	500 mg Doripenem 1 Hour Infusion	500 mg Doripenem 4 Hour Infusion	1000 mg Doripenem 1 Hour Infusion	1000 mg Doripenem 4 Hour Infusion
Arm/Group Description	Probability of target attainment (40%fT>MIC) against Gram-negative pathogens using Monte Carlo simulations	Probability of target attainment (40%fT>MIC) against Gram-negative pathogens using Monte Carlo simulations	Probability of target attainment (40%fT>MIC) against Gram-negative pathogens using Monte Carlo simulations	Probability of target attainment (40%fT>MIC) against Gram-negative pathogens using Monte Carlo simulations
Measure Participants	5	5	6	6
E. coli MIC: 0.06 mg/L	1	1	1	1
K. pneumoniae MIC: 0.12 mg/L	0.99	1	1	1
P. mirabilis MIC: 0.50 mg/L	0.99	1	0.99	1
E. cloacae MIC: 0.25 mg/L	0.99	1	0.99	1
S. marcescens MIC: 0.25 mg/L	0.99	1	0.99	0.99
P. aeruginosa MIC: 4 mg/L	0.55	0.63	0.87	0.94

3. Primary Outcome

Title	Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients
Description	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.
Time Frame	1, 4, 6, 8 hours after at least two doses of drug

Outcome Measure Data

Analysis Population Description

Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing.

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg	Combined Results for Both 500 and 1000 mg
Arm/Group Description	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results
Measure Participants	5	6	11
Mean (Standard Deviation) [hour^-1]	0.36 (0.14)	0.38 (0.20)	0.37 (0.17)

4. Primary Outcome

Title	Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients
Description	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.
Time Frame	1, 4, 6, 8 hours after at least two doses of drug

Outcome Measure Data

Analysis Population Description

Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing.

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg	Combined Results for Both 500 and 1000 mg
Arm/Group Description	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results
Measure Participants	5	6	11
Mean (Standard Deviation) [hours]	2.2 (0.84)	2.4 (1.3)	2.3 (1.1)

5. Primary Outcome

Title	Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients
Description	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.
Time Frame	1, 4, 6, 8 hours after at least two doses of drug

Outcome Measure Data

Analysis Population Description

Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing.

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg	Combined Results for Both 500 and 1000 mg
Arm/Group Description	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results
Measure Participants	5	6	11
Mean (Standard Deviation) [Liters/hour]	11.9 (2.2)	16.6 (6.8)	14.4 (5.6)

6. Primary Outcome

Title	Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients
Description	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.
Time Frame	1, 4, 6, 8 hours after at least two doses of drug

Outcome Measure Data

Analysis Population Description

Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing.

Arm/Group Title	Doripenem 500 mg	Doripenem 1000 mg	Combined Results for Both 500 and 1000 mg
Arm/Group Description	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results
Measure Participants	5	6	11
Mean (Standard Deviation) [milligrams * hour/liters]	47.1 (13.2)	66.4 (33.1)	57.6 (26.8)

Adverse Events

Arm/Group Title	Doripenem 500 mg		Doripenem 1000 mg
Arm/Group Description	pharmacokinetics/pharmacodynamics		pharmacokinetics/pharmacodynamics
All Cause Mortality
	Doripenem 500 mg		Doripenem 1000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Doripenem 500 mg		Doripenem 1000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Doripenem 500 mg		Doripenem 1000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.