Trial Outcomes & Findings for Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients (NCT NCT01401010)

NCT ID: NCT01401010

Last Updated: 2015-10-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

12 participants

Primary outcome timeframe

1, 4, 6, 8 hours after at least two doses of drug

Results posted on

2015-10-14

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Doripenem 500 mg pharmacokinetics/pharmacodynamics	Doripenem 1000 mg pharmacokinetics/pharmacodynamics
Overall Study STARTED	6	6
Overall Study COMPLETED	5	6
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Doripenem 500 mg pharmacokinetics/pharmacodynamics	Doripenem 1000 mg pharmacokinetics/pharmacodynamics
Overall Study Could not interpret assay results	1	0

Baseline Characteristics

Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Doripenem 500 mg n=5 Participants pharmacokinetics/pharmacodynamics	Doripenem 1000 mg n=6 Participants pharmacokinetics/pharmacodynamics	Total n=11 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Age, Continuous	49 years STANDARD_DEVIATION 17 • n=5 Participants	49 years STANDARD_DEVIATION 18 • n=7 Participants	49 years STANDARD_DEVIATION 17.5 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment United States	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants

PRIMARY outcome

Timeframe: 1, 4, 6, 8 hours after at least two doses of drug

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

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.

Outcome measures

Outcome measures
Measure	Doripenem 500 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Doripenem 1000 mg n=6 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Combined Results for Both 500 and 1000 mg n=11 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results	1000 mg Doripenem 4 Hour Infusion Probability of target attainment (40%fT\>MIC) against Gram-negative pathogens using Monte Carlo simulations
Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients	36.7 Liters Standard Deviation 15.9	49.9 Liters Standard Deviation 18.1	43.9 Liters Standard Deviation 17.7	—

PRIMARY outcome

Timeframe: 1, 4, 6, 8 hours after at least two doses of drug

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

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.

Outcome measures

Outcome measures
Measure	Doripenem 500 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Doripenem 1000 mg n=6 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Combined Results for Both 500 and 1000 mg n=11 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results	1000 mg Doripenem 4 Hour Infusion Probability of target attainment (40%fT\>MIC) against Gram-negative pathogens using Monte Carlo simulations
Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients	0.36 hour^-1 Standard Deviation 0.14	0.38 hour^-1 Standard Deviation 0.20	0.37 hour^-1 Standard Deviation 0.17	—

PRIMARY outcome

Timeframe: 1, 4, 6, 8 hours after at least two doses of drug

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

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.

Outcome measures

Outcome measures
Measure	Doripenem 500 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Doripenem 1000 mg n=6 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Combined Results for Both 500 and 1000 mg n=11 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results	1000 mg Doripenem 4 Hour Infusion Probability of target attainment (40%fT\>MIC) against Gram-negative pathogens using Monte Carlo simulations
Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients	2.2 hours Standard Deviation 0.84	2.4 hours Standard Deviation 1.3	2.3 hours Standard Deviation 1.1	—

PRIMARY outcome

Timeframe: 1, 4, 6, 8 hours after at least two doses of drug

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

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.

Outcome measures

Outcome measures
Measure	Doripenem 500 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Doripenem 1000 mg n=6 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Combined Results for Both 500 and 1000 mg n=11 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results	1000 mg Doripenem 4 Hour Infusion Probability of target attainment (40%fT\>MIC) against Gram-negative pathogens using Monte Carlo simulations
Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients	11.9 Liters/hour Standard Deviation 2.2	16.6 Liters/hour Standard Deviation 6.8	14.4 Liters/hour Standard Deviation 5.6	—

PRIMARY outcome

Timeframe: 1, 4, 6, 8 hours after at least two doses of drug

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

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.

Outcome measures

Outcome measures
Measure	Doripenem 500 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Doripenem 1000 mg n=6 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Combined Results for Both 500 and 1000 mg n=11 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results	1000 mg Doripenem 4 Hour Infusion Probability of target attainment (40%fT\>MIC) against Gram-negative pathogens using Monte Carlo simulations
Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients	47.1 milligrams * hour/liters Standard Deviation 13.2	66.4 milligrams * hour/liters Standard Deviation 33.1	57.6 milligrams * hour/liters Standard Deviation 26.8	—

SECONDARY outcome

Timeframe: 1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters

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

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.

Outcome measures

Outcome measures
Measure	Doripenem 500 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 500mg Dosing	Doripenem 1000 mg n=5 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing	Combined Results for Both 500 and 1000 mg n=6 Participants Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results	1000 mg Doripenem 4 Hour Infusion n=6 Participants Probability of target attainment (40%fT\>MIC) against Gram-negative pathogens using Monte Carlo simulations
Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) E. coli MIC: 0.06 mg/L	1 probability of target attainment	1 probability of target attainment	1 probability of target attainment	1 probability of target attainment
Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) K. pneumoniae MIC: 0.12 mg/L	0.99 probability of target attainment	1 probability of target attainment	1 probability of target attainment	1 probability of target attainment
Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) P. mirabilis MIC: 0.50 mg/L	0.99 probability of target attainment	1 probability of target attainment	0.99 probability of target attainment	1 probability of target attainment
Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) E. cloacae MIC: 0.25 mg/L	0.99 probability of target attainment	1 probability of target attainment	0.99 probability of target attainment	1 probability of target attainment
Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) S. marcescens MIC: 0.25 mg/L	0.99 probability of target attainment	1 probability of target attainment	0.99 probability of target attainment	0.99 probability of target attainment
Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC)) P. aeruginosa MIC: 4 mg/L	0.55 probability of target attainment	0.63 probability of target attainment	0.87 probability of target attainment	0.94 probability of target attainment

Adverse Events

Doripenem 500 mg

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Doripenem 1000 mg

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Gary E Stein

Michigan State University

Phone: 517-353-5126

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place