Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01401010

Enrollment

Registered

2011-07-25

Start date

2010-08-31

Completion date

2012-02-29

Last updated

2015-10-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Febrile Neutropenia

Keywords

neutropenia, doripenem

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))

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

Interventions

DRUGDoripenem

500 mg every 8 hours

DRUGdoripenem

1000 mg every 8 hours

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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.
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

Measure	Time frame	Description
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.

Countries

United States

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.

Participants by arm

Arm	Count
Doripenem 500 mg pharmacokinetics/pharmacodynamics	5
Doripenem 1000 mg pharmacokinetics/pharmacodynamics	6
Total	11

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Could not interpret assay results	1	0

Baseline characteristics

Characteristic	Doripenem 1000 mg	Doripenem 500 mg	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	0 Participants	1 Participants
Age, Categorical Between 18 and 65 years	5 Participants	5 Participants	10 Participants
Age, Continuous	49 years STANDARD_DEVIATION 18	49 years STANDARD_DEVIATION 17	49 years STANDARD_DEVIATION 17.5
Region of Enrollment United States	6 participants	5 participants	11 participants
Sex: Female, Male Female	0 Participants	3 Participants	3 Participants
Sex: Female, Male Male	6 Participants	2 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 5	0 / 6
serious Total, serious adverse events	0 / 5	0 / 6

Outcome results

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.

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