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

Traumatic Brain Injury Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04836481
• Other study ID #: 2020-0744
• Status: Completed
• Start date: January 1, 2021
• Est. completion date: October 1, 2023

Study information

• Verified date: February 2024
• Source: University of Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: October 1, 2023
• Est. primary completion date: May 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

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.

Locations

Country	Name	City	State
United States	University of Cincinnati Medical Center	Cincinnati	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
University of Cincinnati	American College of Clinical Pharmacy

Country where clinical trial is conducted

United States, 

References & Publications (18)

Barletta JF, Mangram AJ, Byrne M, Sucher JF, Hollingworth AK, Ali-Osman FR, Shirah GR, Haley M, Dzandu JK. Identifying augmented renal clearance in trauma patients: Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system. J Trauma Acute Care Surg. 2017 Apr;82(4):665-671. doi: 10.1097/TA.0000000000001387. — View Citation

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580. — View Citation

Cook AM, Hatton-Kolpek J. Augmented Renal Clearance. Pharmacotherapy. 2019 Mar;39(3):346-354. doi: 10.1002/phar.2231. Epub 2019 Mar 11. — View Citation

Cotta MO, Abdul-Aziz MH, Frey OR, Sime FB, Roberts JA, Roehr AC. What Are the Predictors for Achieving Therapeutic Levetiracetam Serum Concentrations in Adult Neurological Patients? Ther Drug Monit. 2020 Aug;42(4):626-630. doi: 10.1097/FTD.000000000000073 — View Citation

Gabriel WM, Rowe AS. Long-term comparison of GOS-E scores in patients treated with phenytoin or levetiracetam for posttraumatic seizure prophylaxis after traumatic brain injury. Ann Pharmacother. 2014 Nov;48(11):1440-4. doi: 10.1177/1060028014549013. Epub — View Citation

Inaba K, Menaker J, Branco BC, Gooch J, Okoye OT, Herrold J, Scalea TM, Dubose J, Demetriades D. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013 Mar;74(3):7 — View Citation

Jones KE, Puccio AM, Harshman KJ, Falcione B, Benedict N, Jankowitz BT, Stippler M, Fischer M, Sauber-Schatz EK, Fabio A, Darby JM, Okonkwo DO. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008 — View Citation

Klein P, Herr D, Pearl PL, Natale J, Levine Z, Nogay C, Sandoval F, Trzcinsky S, Atabaki SM, Tsuchida T, van den Anker J, Soldin SJ, He J, McCarter R. Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy. Ep — View Citation

May CC, Arora S, Parli SE, Fraser JF, Bastin MT, Cook AM. Augmented Renal Clearance in Patients with Subarachnoid Hemorrhage. Neurocrit Care. 2015 Dec;23(3):374-9. doi: 10.1007/s12028-015-0127-8. — View Citation

Ramael S, Daoust A, Otoul C, Toublanc N, Troenaru M, Lu ZS, Stockis A. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia. 2006 Jul;47(7):1128-35. doi: 10.1111/j.1528-1167.2006.00586.x. — View Citation

Rowe AS, Goodwin H, Brophy GM, Bushwitz J, Castle A, Deen D, Johnson D, Lesch C, Liang N, Potter E, Roels C, Samaan K, Rhoney DH; Neurocritical Care Society Pharmacy Section. Seizure prophylaxis in neurocritical care: a review of evidence-based support. Pharmacotherapy. 2014;34(4):396-409. doi: 10.1002/phar.1374. Epub 2013 Nov 26. — View Citation

Spencer DD, Jacobi J, Juenke JM, Fleck JD, Kays MB. Steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients. Pharmacotherapy. 2011 Oct;31(10):934-41. doi: 10.1592/phco.31.10.934. — View Citation

Steinhoff BJ, Staack AM. Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience. Ther Adv Neurol Disord. 2019 Sep 9;12:1756286419873518. doi: 10.1177/1756286419873518. eCollection 2019. — View Citation

Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010 Apr;12(2):165-72. doi: 10.1007/s12028-009-9304-y. — View Citation

Tong X, Patsalos PN. A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain. Br J Pharmacol. 2001 Jul;133(6):867-74. doi: 10.1038/sj.bjp.0704141. — View Citation

Udy A, Boots R, Senthuran S, Stuart J, Deans R, Lassig-Smith M, Lipman J. Augmented creatinine clearance in traumatic brain injury. Anesth Analg. 2010 Dec;111(6):1505-10. doi: 10.1213/ANE.0b013e3181f7107d. Epub 2010 Nov 3. — View Citation

Uges JW, van Huizen MD, Engelsman J, Wilms EB, Touw DJ, Peeters E, Vecht CJ. Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus. Epilepsia. 2009 Mar;50(3):415-21. doi: 10.1111/j.1528-1167.2008.01889.x. Epub 2 — View Citation

Zangbar B, Khalil M, Gruessner A, Joseph B, Friese R, Kulvatunyou N, Wynne J, Latifi R, Rhee P, O'Keeffe T. Levetiracetam Prophylaxis for Post-traumatic Brain Injury Seizures is Ineffective: A Propensity Score Analysis. World J Surg. 2016 Nov;40(11):2667- — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

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