A Pharmacokinetic Analysis of Levetiracetam Prophylaxis in Critically Ill Patients With Severe Traumatic Brain Injury

February 28, 2024 updated by: Sarah Schuman Harlan, University of Cincinnati
This study aims is to describe the pharmacokinetic properties of levetiracetam through measurement of serum concentrations in critically ill, severe traumatic brain injury patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Levetiracetam (LEV) is widely used for the prevention and treatment of seizures given its favorable pharmacokinetic profile. A strong correlation between serum concentrations and clinical efficacy has yet to be established; however, a target of 6-20 g/mL is recommended. Limited evidence exists supporting an optimal dosing strategy to achieve these target concentrations in neurocritically ill patients. Previous pharmacokinetic models suggest LEV 1000 mg every 8 hours achieves the highest proportion of therapeutic serum concentrations, but this dosing strategy has not been clinically studied in neurocritically ill patients. Additionally, only one phase two study has evaluated LEV pharmacokinetics in severe traumatic brain injury (TBI).

The aim of this study is to describe the pharmacokinetic properties of LEV through measurement of serum concentrations in critically ill, severe TBI patients. Secondarily, this study aims to develop a population pharmacokinetic model aimed at characterizing LEV dose optimization in severe TBI. An exploratory aim is to evaluate LEV pharmacodynamics in severe TBI patients through evaluation of physiologic, electrophysiologic and biochemical changes using multimodal monitoring or surface electroencephalogram (EEG), as available. A subgroup analysis will evaluate LEV pharmacokinetics in severe TBI patients with augmented renal clearance (ARC).

This prospective, single-center pharmacokinetic and pharmacodynamic study will include critically ill patients receiving intravenous LEV for seizure prophylaxis following severe TBI. Patients with severe TBI qualifying for multimodal monitoring will receive LEV 1000 mg every 8 hours (LEV8) per institutional practice. All other severe TBI patients will receive LEV 1000 mg every 12 hours (LEV12) according to institution practice. Patients with renal dysfunction (creatinine clearance < 50 mL/min) will be excluded. All patients will have five serum samples collected following the sixth or greater consecutive dose. Patients receiving LEV8 will have samples collected at 0.5, 1, 4, 6, and 8 hours. Patients receiving LEV12 will have samples collected at 0.5, 1, 4, 8, and 12 hours. Serum concentrations will be analyzed with pharmacokinetic modeling and Monte Carlo simulations. LEV pharmacodynamics will be evaluated in patients receiving multimodal monitoring or surface EEG, as available. Analysis of ARC will include patients with Augmented Renal Clearance in Trauma Intensive Care (ARTIC) score >6 during sampling.

Study Type

Observational

Enrollment (Actual)

10

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

The target population for this study will be patients with severe traumatic brain injury, defined as a post-resuscitation GCS 3-8 with or without CT abnormalities who are receiving intravenous levetiracetam 1000 mg every 8 or every 12 hours for seizure prophylaxis.

Description

Inclusion Criteria:

  • Admitted to the neurosurgical intensive care unit or surgical intensive care unit following severe traumatic brain injury (post-resuscitation GCS 3-8 with or without CT abnormalities)
  • Receiving intravenous levetiracetam for seizure prophylaxis at a dose of 1000 mg every 12 hours or 1000 mg every 8 hours at time of enrollment

Exclusion Criteria:

  • Known history of epilepsy or seizure disorder
  • Taking antiseizure medication prior to admission
  • Taking medication with known effect on levetiracetam pharmacokinetics including carbamazepine, phenytoin, oxcarbazepine, mefloquine, methotrexate, mianserin, or orlistat
  • Weight < 50 kg
  • Anticipated survival <72 hours from injury, as deemed by the primary neurosurgical provider
  • Acute Kidney Injury (Scr rise > 0.3 mg/dL from baseline) or creatinine clearance <50 mL/min at time of enrollment
  • Prisoners
  • Pregnant

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
LEV8
Levetiracetam 1000 mg every 8 hours
Other: Serum Sample Collection
Each patient will have 5 serum samples collected for analysis after a minimum six consecutive doses. Patients receiving LEV8 will have sampled collected at hours 0.5, 1, 4, 6, and 8. Patients receiving LEV12 will have sampled collected at hours 0.5, 1, 4, 8, and 12.
LEV12
Levetiracetam 1000 mg every 12 hours
Other: Serum Sample Collection
Each patient will have 5 serum samples collected for analysis after a minimum six consecutive doses. Patients receiving LEV8 will have sampled collected at hours 0.5, 1, 4, 6, and 8. Patients receiving LEV12 will have sampled collected at hours 0.5, 1, 4, 8, and 12.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum Levetiracetam Concentration 1
Time Frame: Hour 0.5
Serum levetiracetam concentration collected at 0.5 hours after target dose for sampling
Hour 0.5
Serum Levetiracetam Concentration 2
Time Frame: Hour 1
Serum levetiracetam concentration collected at hour 1 after target dose for sampling
Hour 1
Serum Levetiracetam Concentration 3
Time Frame: Hour 4
Serum levetiracetam concentration collected at hour 4 after target dose for sampling
Hour 4
Serum Levetiracetam Concentration 4
Time Frame: Hour 6-8
Serum levetiracetam concentration collected at hour 6 (patients receiving every 8 hour levetiracetam) or hour 8 (patients receiving every 12 hour levetiracetam)
Hour 6-8
Serum Levetiracetam Concentration 5
Time Frame: Hour 8-12
Serum levetiracetam concentration collected at hour 8 (patients receiving every 8 hour levetiracetam) or hour 12 (patients receiving every 12 hour levetiracetam)
Hour 8-12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intracranial Pressure
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Perfusion Pressure
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Pressure Reactivity Index
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Blood Flow
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Microdialysis Glucose Concentration
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Microdialysis Pyruvate Concentration
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Microdialysis Lactate Concentration
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Microdialysis Glutamate Concentration
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
Cerebral Microdialysis Glycerol Concentration
Time Frame: Baseline to Day 7
Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis
Baseline to Day 7
ARTIC Score
Time Frame: Hour 0.5 (Collected at time of first serum sample collection)
Calculated ARTIC score
Hour 0.5 (Collected at time of first serum sample collection)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Cincinnati

Collaborators

American College of Clinical Pharmacy

Investigators

  • Principal Investigator: Sarah Schuman Harlan, PharmD, University of Cincinnati
  • Principal Investigator: Shaun Keegan, PharmD, University of Cincinnati
  • Principal Investigator: Carolyn Philpott, PharmD, University of Cincinnati

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2021

Primary Completion (Actual)

May 1, 2022

Study Completion (Actual)

October 1, 2023

Study Registration Dates

First Submitted

December 10, 2020

First Submitted That Met QC Criteria

April 7, 2021

First Posted (Actual)

April 8, 2021

Study Record Updates

Last Update Posted (Estimated)

February 29, 2024

Last Update Submitted That Met QC Criteria

February 28, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2020-0744

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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