Levetiracetam Pharmacokinetics and Brain Uptake in a Lateral Fluid Percussion Injury Rat Model.
Lisa D ColesPatricia G SalettiChristos Panagiotis LisgarasPablo M Casillas-EspinosaWei LiuQianyun LiNigel C JonesSandy ShultzIdrish AliRhys BradyGlenn YamakawaMatt HudsonJuliana SilvaEmma BraineUsha MishraJames C CloydTerence J O'brienSolomon L MoshéAristea S GalanopoulouPublished in: The Journal of pharmacology and experimental therapeutics (2023)
Post-traumatic epilepsy (PTE) occurs in some patients following moderate/severe traumatic brain injury (TBI). While 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 following 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 7days. Blood and parietal cortical samples were collected at specified timepoints throughout the study. LEV concentrations in plasma and brain were measured using validated HPLC-MS/MS methods. Non-compartmental analysis and a compartmental PK modeling approach were utilized. Brain-to-plasma ratios ranged from 0.54-1.4-1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 mL/hr/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.
Keyphrases
- severe traumatic brain injury
- white matter
- traumatic brain injury
- ms ms
- resting state
- emergency department
- newly diagnosed
- minimally invasive
- ultrasound guided
- machine learning
- high glucose
- mass spectrometry
- brain injury
- health information
- quality improvement
- current status
- combination therapy
- high resolution
- big data