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 Moshé; Aristea S Galanopoulou; EpiBioS4Rx Study Group

doi:10.1124/jpet.122.001377

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

J Pharmacol Exp Ther. 2023 Aug;386(2):259-265. doi: 10.1124/jpet.122.001377. Epub 2023 Jun 14.

Authors

Lisa D Coles¹, Patricia G Saletti², Christos Panagiotis Lisgaras², Pablo M Casillas-Espinosa², Wei Liu², Qianyun Li², Nigel C Jones², Sandy Shultz², Idrish Ali², Rhys Brady², Glenn Yamakawa², Matt Hudson², Juliana Silva², Emma Braine², Usha Mishra², James C Cloyd², Terence J O'Brien², Solomon L Moshé², Aristea S Galanopoulou²; EpiBioS4Rx Study Group

Affiliations

¹ 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 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.).

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 naïve 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. Naïve 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anticonvulsants / therapeutic use
Brain
Brain Injuries, Traumatic* / complications
Brain Injuries, Traumatic* / drug therapy
Disease Models, Animal
Epilepsy, Post-Traumatic* / drug therapy
Levetiracetam
Percussion
Rats
Rats, Sprague-Dawley
Tandem Mass Spectrometry

Substances

Levetiracetam
Anticonvulsants

Abstract

Publication types

MeSH terms

Substances

Grants and funding