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

Study Overview
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Brief Summary
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This study aims is to describe the pharmacokinetic properties of levetiracetam through measurement of serum concentrations in critically ill, severe traumatic brain injury patients.

Detailed Description
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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.

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

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Other: Serum Sample Collection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| LEV8<br>Levetiracetam 1000 mg every 8 hours | Other: Serum Sample Collection<br>* 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.<br>|
| LEV12<br>Levetiracetam 1000 mg every 12 hours | Other: Serum Sample Collection<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Levetiracetam Concentration 1 | Serum levetiracetam concentration collected at 0.5 hours after target dose for sampling | Hour 0.5 | 
| Serum Levetiracetam Concentration 2 | Serum levetiracetam concentration collected at hour 1 after target dose for sampling | Hour 1 | 
| Serum Levetiracetam Concentration 3 | Serum levetiracetam concentration collected at hour 4 after target dose for sampling | Hour 4 | 
| Serum Levetiracetam Concentration 4 | 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 | 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 | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Perfusion Pressure | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Pressure Reactivity Index | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Blood Flow | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Microdialysis Glucose Concentration | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Microdialysis Pyruvate Concentration | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Microdialysis Lactate Concentration | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Microdialysis Glutamate Concentration | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| Cerebral Microdialysis Glycerol Concentration | Collected at baseline and at each time of serum sample collection for pharmacodynamic analysis | Baseline to Day 7 | 
| ARTIC Score | Calculated ARTIC score | Hour 0.5 (Collected at time of first serum sample collection) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seizure Prophylaxis, Pharmacokinetic, Levetiracetam