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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))
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Doripenem 500 mg | Active Comparator | pharmacokinetics/pharmacodynamics |
|
| Doripenem 1000 mg | Active Comparator | pharmacokinetics/pharmacodynamics |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Doripenem | Drug | 500 mg every 8 hours |
|
|
| 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. |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gary Stein, PharmD | Michigan State University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sparrow Hospital | Lansing | Michigan | 48910 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Doripenem 500 mg | pharmacokinetics/pharmacodynamics |
| FG001 | Doripenem 1000 mg | pharmacokinetics/pharmacodynamics |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Doripenem 500 mg | pharmacokinetics/pharmacodynamics |
| BG001 | Doripenem 1000 mg | pharmacokinetics/pharmacodynamics |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing. | Posted | Mean | Standard Deviation | Liters | 1, 4, 6, 8 hours after at least two doses of drug |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Doripenem 500 mg | pharmacokinetics/pharmacodynamics |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gary E Stein | Michigan State University | 517-353-5126 | Gary.Stein@hc.msu.edu |
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| ID | Term |
|---|---|
| D064147 | Febrile Neutropenia |
| D009503 | Neutropenia |
| ID | Term |
|---|---|
| D000380 | Agranulocytosis |
| D007970 | Leukopenia |
| D000095542 | Cytopenia |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D000077726 | Doripenem |
| ID | Term |
|---|---|
| D015780 | Carbapenems |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 |
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| doripenem | Drug | 1000 mg every 8 hours |
|
|
| 1, 4, 6, 8 hours after at least two doses of drug |
| 1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters |
| BG002 |
| Total |
Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Who Received 1000 mg Dosing |
| OG002 | Combined Results for Both 500 and 1000 mg | Mean (SD) Doripenem Pharmacokinetic (PK) Parameters in Febrile Neutropenic Patients Combined Results |
|
|
| 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. | Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing. | Posted | Number | probability of target attainment | 1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters |
|
|
|
| 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. | Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing. | Posted | Mean | Standard Deviation | hour^-1 | 1, 4, 6, 8 hours after at least two doses of drug |
|
|
|
| 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. | Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing. | Posted | Mean | Standard Deviation | hours | 1, 4, 6, 8 hours after at least two doses of drug |
|
|
|
| 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. | Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing. | Posted | Mean | Standard Deviation | Liters/hour | 1, 4, 6, 8 hours after at least two doses of drug |
|
|
|
| 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. | Each subject received drug and had serum samples drawn at 1, 4, 6, 8 hours after dosing. | Posted | Mean | Standard Deviation | milligrams * hour/liters | 1, 4, 6, 8 hours after at least two doses of drug |
|
|
|
| 0 |
| 5 |
| 0 |
| 5 |
| EG001 | Doripenem 1000 mg | pharmacokinetics/pharmacodynamics | 0 | 6 | 0 | 6 |
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| D006425 |
| Hemic and Lymphatic Diseases |
| D007960 | Leukocyte Disorders |
| Organic Chemicals |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| K. pneumoniae MIC: 0.12 mg/L |
|
| P. mirabilis MIC: 0.50 mg/L |
|
| E. cloacae MIC: 0.25 mg/L |
|
| S. marcescens MIC: 0.25 mg/L |
|
| P. aeruginosa MIC: 4 mg/L |
|