A Phase 4 interventional study of Doripenem and doripenem in Febrile Neutropenia, sponsored by Gary E. Stein, Pharm.D.. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-10-14.
Sponsored by Gary E. Stein, Pharm.D. · Phase 4, Interventional, and Treatment
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
396 studies on the registry are indexed under Neutropenia; 57 are open to participants now.
This study's enrollment of 12 is below the median of 93 across 276 interventional studies indexed under Neutropenia.
Browse Neutropenia studies →Gary E. Stein, Pharm.D. is the lead sponsor of 4 studies on the registry; none are open to participants now.
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Exclusion Criteria:
pharmacokinetics/pharmacodynamics
Drug: Doripenem
pharmacokinetics/pharmacodynamics
Drug: doripenem
500 mg every 8 hours
Also known as: Doribac
1000 mg every 8 hours
Also known as: Doribac
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 1, 4, 6, 8 hours after at least two doses of drug
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.
Time frame: 1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters
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.
| Milestone | Doripenem 500 mg | Doripenem 1000 mg |
|---|---|---|
| Started | 6 | 6 |
| Completed | 5 | 6 |
| Not completed | 1 | 0 |
| Withdrew: Could not interpret assay results | 1 | 0 |
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.
| Liters | Doripenem 500 mg | Doripenem 1000 mg | Combined Results for Both 500 and 1000 mg |
|---|---|---|---|
| Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients | 36.7 ± 15.9 | 49.9 ± 18.1 | 43.9 ± 17.7 |
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.
| probability of target attainment | 500 mg Doripenem 1 Hour Infusion | 500 mg Doripenem 4 Hour Infusion | 1000 mg Doripenem 1 Hour Infusion | 1000 mg Doripenem 4 Hour Infusion |
|---|---|---|---|---|
| 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 |
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.
| hour^-1 | Doripenem 500 mg | Doripenem 1000 mg | Combined Results for Both 500 and 1000 mg |
|---|---|---|---|
| Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients | 0.36 ± 0.14 | 0.38 ± 0.20 | 0.37 ± 0.17 |
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.
| hours | Doripenem 500 mg | Doripenem 1000 mg | Combined Results for Both 500 and 1000 mg |
|---|---|---|---|
| Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients | 2.2 ± 0.84 | 2.4 ± 1.3 | 2.3 ± 1.1 |
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.
| Liters/hour | Doripenem 500 mg | Doripenem 1000 mg | Combined Results for Both 500 and 1000 mg |
|---|---|---|---|
| Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients | 11.9 ± 2.2 | 16.6 ± 6.8 | 14.4 ± 5.6 |
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.
| milligrams * hour/liters | Doripenem 500 mg | Doripenem 1000 mg | Combined Results for Both 500 and 1000 mg |
|---|---|---|---|
| Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients | 47.1 ± 13.2 | 66.4 ± 33.1 | 57.6 ± 26.8 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Doripenem 500 mg | — | 0/5 (0%) | 0/5 (0%) |
| Doripenem 1000 mg | — | 0/6 (0%) | 0/6 (0%) |
| Age, Categorical(Participants) | Doripenem 500 mg | Doripenem 1000 mg | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 5 | 5 | 10 |
| >=65 years | 0 | 1 | 1 |
| Age, Continuous(years) | Doripenem 500 mg | Doripenem 1000 mg | Total |
|---|---|---|---|
| Mean | 49 ± 17 | 49 ± 18 | 49 ± 17.5 |
| Sex: Female, Male(Participants) | Doripenem 500 mg | Doripenem 1000 mg | Total |
|---|---|---|---|
| Female | 3 | 0 | 3 |
| Male | 2 | 6 | 8 |
| Region of Enrollment(participants) | Doripenem 500 mg | Doripenem 1000 mg | Total |
|---|---|---|---|
| United States | 5 | 6 | 11 |
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Gary E. Stein, Pharm.D.