Pharmacokinetic/Pharmacodynamic Study of Doripenem in Febrile Neutropenic Patients

NCT ID: NCT01401010

Last Updated: 2015-10-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-08-31
• Study Completion Date: 2012-02-29

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

Conditions

Febrile Neutropenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Doripenem 500 mg

pharmacokinetics/pharmacodynamics

Group Type: ACTIVE_COMPARATOR

Doripenem

Intervention Type: DRUG

500 mg every 8 hours

Doripenem 1000 mg

pharmacokinetics/pharmacodynamics

Group Type: ACTIVE_COMPARATOR

doripenem

Intervention Type: DRUG

1000 mg every 8 hours

Interventions

Doripenem

500 mg every 8 hours

Intervention Type: DRUG

doripenem

1000 mg every 8 hours

Intervention Type: DRUG

Other Intervention Names

Doribac; Doribac

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gary E. Stein, Pharm.D.

OTHER

Sponsor Role: lead

Responsible Party

Gary E. Stein, Pharm.D.

Professor of Medicine and Pharmacology

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Gary Stein, PharmD

Role: PRINCIPAL_INVESTIGATOR

Michigan State University

Locations

Sparrow Hospital

Lansing, Michigan, United States

Countries

United States

Other Identifiers

DORIBAC4006a

Identifier Type: -

Identifier Source: org_study_id