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The Journal of pharmacology and experimental therapeutics
08, 2023;386 (2): 259-265.

Levetiracetam Pharmacokinetics and Brain Uptake in a Lateral Fluid Percussion Injury Rat Model.

Lisa D Coles, Patricia G Saletti, Christos Panagiotis Lisgaras, Pablo M Casillas-Espinosa, Wei Liu, Qianyun Li, Nigel C Jones, Sandy Shultz, Idrish Ali, Rhys Brady, Glenn Yamakawa, Matt Hudson, Juliana Silva, Emma Braine, Usha Mishra, James C Cloyd, Terence J O'Brien, Solomon L Mosh��, Aristea S Galanopoulou, EpiBioS4Rx Study Group
Author Information
  1. Lisa D Coles: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.) durh0016@umn.edu.
  2. Patricia G Saletti: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  3. Christos Panagiotis Lisgaras: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  4. Pablo M Casillas-Espinosa: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  5. Wei Liu: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  6. Qianyun Li: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  7. Nigel C Jones: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  8. Sandy Shultz: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  9. Idrish Ali: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  10. Rhys Brady: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  11. Glenn Yamakawa: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  12. Matt Hudson: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  13. Juliana Silva: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  14. Emma Braine: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  15. Usha Mishra: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  16. James C Cloyd: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  17. Terence J O'Brien: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  18. Solomon L Mosh��: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.).
  19. Aristea S Galanopoulou: University of Minnesota Twin Cities, Minneapolis, Minnesota (L.D.C., U.M., J.C.C.); Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy (P.G.S., C.P.L., W.L., Q.L., S.L.M., A.S.G.), Isabelle Rapin Division of Child Neurology (S.L.M., A.S.G.), Dominick P. Purpura Department of Neuroscience (S.L.M., A.S.G.), and Department of Pediatrics (S.L.M.), Albert Einstein College of Medicine, Bronx, New York; Department of Neuroscience, Monash University, Melbourne, Australia (P.M.C.-E., S.S., R.B., G.Y., M.H., J.S., E.B., T.J.O.); and The University of Melbourne, Parkville, Australia (R.B., G.Y., M.H., J.S., E.B., T.J.O.). ORCID
PMID: 37316328 DOI: 10.1124/jpet.122.001377

Abstract

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in na��ve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Na��ve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies.

References

  1. Neurobiol Dis. 2019 Mar;123:100-109 [PMID: 30099094]
  2. Epileptic Disord. 2003 May;5 Suppl 1:S9-16 [PMID: 12915336]
  3. Neuroscience. 2006 Jun 30;140(2):685-97 [PMID: 16650603]
  4. Br J Pharmacol. 2001 Jul;133(6):867-74 [PMID: 11454660]
  5. Brain Inj. 2016;30(2):156-8 [PMID: 26619246]
  6. Drug Metab Dispos. 2019 Jan;47(1):38-44 [PMID: 30389729]
  7. Eur J Pharm Sci. 2018 Mar 30;115:339-344 [PMID: 29391214]
  8. JAMA Netw Open. 2021 Dec 1;4(12):e2140191 [PMID: 34964854]
  9. Neurobiol Dis. 2019 Mar;123:86-99 [PMID: 29936231]
  10. J Neuroinflammation. 2020 Jun 17;17(1):193 [PMID: 32552898]
  11. Mol Pharmacol. 2009 Aug;76(2):215-28 [PMID: 19483103]
  12. Neurobiol Dis. 2019 Mar;123:8-19 [PMID: 30121231]
  13. J Head Trauma Rehabil. 2009 Nov-Dec;24(6):439-51 [PMID: 19940677]
  14. Epilepsy Behav. 2012 Aug;24(4):457-61 [PMID: 22771222]
  15. Epilepsy Res. 2015 Aug;114:52-8 [PMID: 26088885]
  16. Epilepsia. 2020 Mar;61(3):359-386 [PMID: 32196665]
  17. J Clin Pharmacol. 2021 Jun;61(6):763-768 [PMID: 33336359]
  18. Seizure. 2017 Jul;49:8-12 [PMID: 28528211]
  19. Neurocrit Care. 2023 Apr;38(2):345-355 [PMID: 36167949]
  20. J Child Neurol. 2009 Aug;24(8):946-51 [PMID: 19264738]
  21. Lancet. 2020 Apr 11;395(10231):1217-1224 [PMID: 32203691]
  22. Epilepsy Curr. 2019 May-Jun;19(3):177-181 [PMID: 31037960]
  23. J Clin Neurosci. 2015 Jun;22(6):959-63 [PMID: 25899652]
  24. J Pharmacol Exp Ther. 1998 Feb;284(2):474-9 [PMID: 9454787]
  25. Neurobiol Dis. 2019 Mar;123:3-7 [PMID: 29625256]
  26. Epilepsia. 2002 Apr;43(4):350-7 [PMID: 11952764]
  27. Seizure. 2019 Feb;65:111-117 [PMID: 30682680]
  28. Xenobiotica. 2004 Mar;34(3):281-300 [PMID: 15204700]
  29. Neuroscience. 1989;28(1):233-44 [PMID: 2761692]

Grants

  1. U54 NS100064/NINDS NIH HHS
  2. R37 NS043209/NINDS NIH HHS
  3. U54 HD090260/NICHD NIH HHS
  4. R01 NS091170/NINDS NIH HHS
  5. R01 NS043209/NINDS NIH HHS

MeSH Term

Rats
Animals
Levetiracetam
Epilepsy, Post-Traumatic
Percussion
Tandem Mass Spectrometry
Rats, Sprague-Dawley
Brain
Brain Injuries, Traumatic
Anticonvulsants
Disease Models, Animal

Chemicals

Levetiracetam
Anticonvulsants
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0LEVbrainPKinjuryTBIratsLFPImodelusedconcentrationsguideepilepsymoderate/severelevetiracetamusstudyEpiBioS4Rxpharmacokineticsuptakeeitherintraperitonealdosefollowedsubcutaneousinfusionparietalusingbolusinjection1studiestargetoptimaltreatmentPost-traumaticPTEoccurspatientstraumaticAlthoughapprovedtherapiespreventepileptogenesiscommonlygivenseizureprophylaxisduegoodsafetyprofileledpartEpilepsyBioinformaticsStudyAntiepileptogenicTherapyProjectobjectiveworkcharacterizena��vecontrollateralfluidpercussionratsingledosesloading7-daySprague-DawleycontrolsinducedleftregionparametersoptimizedNa��vereceived7daysBloodcorticalsamplescollectedspecifiedtimepointsthroughoutplasmameasuredvalidatedhigh-performanceliquidchromatography-tandemmassspectrometryHPLC-MS/MSmethodsNoncompartmentalanalysisnaive-pooledcompartmentalmodelingapproachBrain-to-plasmaratiosranged0544wellfitone-compartmentfirst-orderabsorptionmodelsclearance112ml/hperkgvolumedistribution293ml/kgsingle-dosepharmacokineticdataselectionlonger-termdrugexposuresconfirmedObtaininginformationearlyscreeningphaseallowedprotocolsSIGNIFICANCESTATEMENT:characterizationanimalpost-traumaticessentialidentifyfutureLevetiracetamPharmacokineticsBrainUptakeLateralFluidPercussionInjuryRatModel

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