Clinical trial NCT04836481: A Pharmacokinetic Analysis of Levetiracetam Prophylaxis in Critically Ill Patients With Severe Traumatic Brain Injury
Official title: A Pharmacokinetic Analysis of Levetiracetam Prophylaxis in Critically Ill Patients With Severe Traumatic Brain Injury
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Traumatic Brain Injury
Keywords: Levetiracetam
Seizure Prophylaxis
Pharmacokinetic
Lead sponsor: University of Cincinnati
Sponsor class: OTHER
Collaborators: name: American College of Clinical Pharmacy
First posted: 2021-04-08
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
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.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Serum Levetiracetam Concentration 1
timeFrame: Hour 0.5
measure: Serum Levetiracetam Concentration 2
timeFrame: Hour 1
measure: Serum Levetiracetam Concentration 3
timeFrame: Hour 4
measure: Serum Levetiracetam Concentration 4
timeFrame: Hour 6-8
measure: Serum Levetiracetam Concentration 5
timeFrame: Hour 8-12
Secondary outcomes:
measure: Intracranial Pressure
timeFrame: Baseline to Day 7
measure: Cerebral Perfusion Pressure
timeFrame: Baseline to Day 7
measure: Pressure Reactivity Index
timeFrame: Baseline to Day 7
measure: Cerebral Blood Flow
timeFrame: Baseline to Day 7
measure: Cerebral Microdialysis Glucose Concentration
timeFrame: Baseline to Day 7
measure: Cerebral Microdialysis Pyruvate Concentration
timeFrame: Baseline to Day 7
measure: Cerebral Microdialysis Lactate Concentration
timeFrame: Baseline to Day 7
measure: Cerebral Microdialysis Glutamate Concentration
timeFrame: Baseline to Day 7
measure: Cerebral Microdialysis Glycerol Concentration
timeFrame: Baseline to Day 7
measure: ARTIC Score
timeFrame: Hour 0.5 (Collected at time of first serum sample collection)
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
Study officials:
affiliation: University of Cincinnati
name: Sarah Schuman Harlan, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cincinnati
name: Shaun Keegan, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cincinnati
name: Carolyn Philpott, PharmD
role: PRINCIPAL_INVESTIGATOR
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