Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01027897
• Collaborator: Ortho-McNeil Janssen Scientific Affairs, LLC (Industry)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 20
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis	Drug: Doripenem	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients With Sepsis at Grady Health System
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Volume of Distribution (Vd) [After 3rd dose of study medication]

   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

2. Clearance (CL) [After 3rd dose of study medication]

   Clearance is the volume of drug removed from the body per unit of time (hrs).

3. Elimination Constant (ke) [after 3rd dose of study drug]

   The elimination rate constant of a drug from the central compartment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Grady Memorial Hospital	Atlanta	Georgia	United States	30303

Sponsors and Collaborators

• Emory University
• Ortho-McNeil Janssen Scientific Affairs, LLC

Investigators

• Principal Investigator: Jeffrey Salomone, MD, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Emory University
• ClinicalTrials.gov Identifier: NCT01027897
• Other Study ID Numbers: IRB00016181a; DORICPK4003
• First Posted: Dec 9, 2009
• Last Update Posted: Jan 27, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by Emory University: Pharmacokinetics; Pharmacodynamics; Doripenem; Trauma; sepsis; Trauma patients with sepsis
• Additional relevant MeSH terms: Sepsis; Toxemia; Doripenem

Study Results

Participant Flow

Recruitment Details	Patients recruited from April 2010 to July 2011. All patients were admitted to the Surgical ICU during the study period

Arm/Group Title	Doripenem Group
Arm/Group Description	Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection
Period Title: Overall Study
STARTED	30
COMPLETED	28
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Doripenem Group
Arm/Group Description	Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 83.3%
>=65 years	5 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.6 (15)
Sex: Female, Male (Count of Participants)
Female	6 20%
Male	24 80%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Volume of Distribution (Vd)
Description	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
Time Frame	After 3rd dose of study medication

Outcome Measure Data

Analysis Population Description

Patients that completed the study and did not have atypical variations in the measurement of serum concentrations were included in the final evaluation

Arm/Group Title	Doripenem Group
Arm/Group Description	Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection
Measure Participants	27
Mean (Standard Deviation) [liters]	28.52 (16.01)

2. Primary Outcome

Title	Clearance (CL)
Description	Clearance is the volume of drug removed from the body per unit of time (hrs).
Time Frame	After 3rd dose of study medication

Outcome Measure Data

Analysis Population Description

Patients that completed the study and did not have atypical variations in the measurement of serum concentrations were included in the final evaluation

Arm/Group Title	Doripenem Group
Arm/Group Description	Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection
Measure Participants	27
Mean (Standard Deviation) [liters per hour]	16.94 (11.4)

3. Primary Outcome

Title	Elimination Constant (ke)
Description	The elimination rate constant of a drug from the central compartment
Time Frame	after 3rd dose of study drug

Outcome Measure Data

Analysis Population Description

Patients that completed the study and did not have atypical variations in the measurement of serum concentrations were included in the final evaluation

Arm/Group Title	Doripenem Group
Arm/Group Description	Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection
Measure Participants	27
Mean (Standard Deviation) [per hour]	1.47 (2.24)

Adverse Events

Arm/Group Title	Doripenem Group
Arm/Group Description	Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection
All Cause Mortality
	Doripenem Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Doripenem Group
	Affected / at Risk (%)	# Events
Total	8/30 (26.7%)
Cardiac disorders
cardiac arrest	1/30 (3.3%)	1
atrial fibrillation	2/30 (6.7%)	2
Gastrointestinal disorders
Lower gastrointestinal	1/30 (3.3%)	1
Renal and urinary disorders
renal failure acute	2/30 (6.7%)	2
Skin and subcutaneous tissue disorders
Post operative wound	1/30 (3.3%)	1
Vascular disorders
deep vein thrombosis	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Doripenem Group
	Affected / at Risk (%)	# Events
Total	0/30 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.