Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients

Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients With Sepsis at Grady Health System

The study hypothesis is to measure how the drug doripenem is cleared from the body of critically ill trauma patients. The investigators will measure blood drug concentrations and calculate how much the drug distributes in the body and how fast it is removed from the body. There is little information on how drugs are cleared in critically ill patients and the wrong dose of a drug could make it ineffective. The investigators will use this information to predict the most reasonable dose to treat infections effectively in these patients.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Doripenem

Detailed Description

Understanding the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of an antibiotic can provide insight into developing appropriate dosing regimens. It is even more imperative at the present time to maximize PK/PD parameters since there are no new novel antimicrobial agents to treat resistant gram-negative infections. This approach allows us to achieve superior PD parameters and treat bacteria that would have been resistant to standard dosing due to higher minimum inhibitory concentrations (MICs).

Doripenem exhibits time-dependent bactericidal activity and the pharmacodynamic parameter predicting clinical and bacteriologic outcomes is the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (T > MIC) of the infecting pathogen Sepsis is known to influence drug pharmacokinetics and pharmacodynamics as a result of changes in hemodynamics, capillary permeability, third spacing, acid-base status, serum proteins, and organ function. Moreover, trauma patients tend to be younger with fewer comorbidities. They are hypermetabolic and are often given aggressive fluid resuscitation resulting in increased renal clearance of drugs and a larger volume of distribution. As a consequence of these differences in PK parameters, the calculated PD parameters will likely differ resulting in sub-optimal T> MIC. For time-dependent antibacterial agents such as doripenem, the T > MIC is one of the most important pharmacodynamic parameters in predicting clinical efficacy, therefore it is imperative to evaluate the PK parameters in this particular population.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients are 18 years of age or older
• Admitted to Emory surgical intensive care unit (ICU) service
• Have a diagnosis of sepsis that requires empiric antimicrobial therapy
• Obtained written informed consent from the patient or a first-degree relative if the patient is unable to give informed consent due to his/her medical condition prior to initiation of any study procedure

Exclusion Criteria:

• Surgical ICU length of stay less than 24 hours
• Acute or chronic renal dysfunction (urine output less than 0.5 mL/kg/hr or calculated creatinine clearance of less than 50 mL/min)
• Pregnancy
• Known allergy to beta-lactam antibiotics
• Non-English-speaking patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doripenem group; Patients will receive doripenem for the treatment of their infection	Drug: Doripenem; Doripenem 1 gm administered over 4 hours X 3 doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of Distribution (Vd)	The Volume of distribution is the calculated volume that the given amount of drug is uniformly distributed in the body to achieve a particular concentration	After 3rd dose of study medication
Clearance (CL)	Clearance is the volume of drug removed from the body per unit of time (hrs).	After 3rd dose of study medication
Elimination Constant (ke)	The elimination rate constant of a drug from the central compartment	after 3rd dose of study drug

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Ortho-McNeil Janssen Scientific Affairs, LLC
• Investigators: Principal Investigator: Jeffrey Salomone, MD, Emory University

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: December 8, 2009
• First Submitted That Met QC Criteria: December 8, 2009
• First Posted (Estimate): December 9, 2009

Study Record Updates

• Last Update Posted (Estimate): January 27, 2014
• Last Update Submitted That Met QC Criteria: December 19, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; sepsis; Trauma; Pharmacodynamics; Doripenem; Trauma patients with sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Anti-Infective Agents; Anti-Bacterial Agents; Doripenem
• Other Study ID Numbers: IRB00016181a; DORICPK4003 (Other Identifier: other)