Clinical trial NCT01401010: Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients
Official title: Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients With Possible Bacterial Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Febrile Neutropenia
Keywords: neutropenia
doripenem
Lead sponsor: Michigan State University
Sponsor class: OTHER
First posted: 2011-07-25
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Mean (SD) Doripenem Pharmacokinetic Volume of Distribution Parameter in Febrile Neutropenic Patients
timeFrame: 1, 4, 6, 8 hours after at least two doses of drug
measure: Mean (SD) Doripenem Pharmacokinetic (PK) Elimination Rate Constant Parameter in Febrile Neutropenic Patients
timeFrame: 1, 4, 6, 8 hours after at least two doses of drug
measure: Mean (SD) Doripenem Pharmacokinetic (PK) Half Life Parameter in Febrile Neutropenic Patients
timeFrame: 1, 4, 6, 8 hours after at least two doses of drug
measure: Mean (SD) Doripenem Pharmacokinetic (PK) Clearance of Drug Parameter in Febrile Neutropenic Patients
timeFrame: 1, 4, 6, 8 hours after at least two doses of drug
measure: Mean (SD) Doripenem Pharmacokinetic (PK) Area Under Serum Curve (mg*h/L) Parameter in Febrile Neutropenic Patients
timeFrame: 1, 4, 6, 8 hours after at least two doses of drug
Secondary outcomes:
measure: Monte Carlo Simulations Tested Against Various Gram-negative Isolates and Reported as Probability of Target Attainment (40% Time (fT) > Minimum Inhibitory Concentrations (MIC))
timeFrame: 1, 4, 6, 8 hours after an infusion of doripenem to determine the PK parameters
Other outcomes:
Locations:
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
Study officials:
affiliation: Michigan State University
name: Gary Stein, PharmD
role: PRINCIPAL_INVESTIGATOR
References: