Abstracts

Rationale: EpiBioS4Rx is a multicenter, international collaboration utilizing a team science approach to identify new therapies to prevent the development of post-traumatic epilepsy (PTE) following traumatic brain injury (TBI).  A preclinical therapy testing platform operated by many institutions has been implemented to enhance reproducibility. This platform allows for early integration of pharmacokinetic (PK) and pharmacodynamic (PD) analyses which can accelerate drug discovery and development by helping to identify lead compounds, accelerating dose finding, scaling doses across species, decreasing costs, and guiding the design of animal and human studies.  As part of EpiBioS4Rx Project 2, we are screening compounds for antiepileptogenic effects using the lateral fluid percussion injury (LFPI) rat model of TBI.  The objective of this work is to utilize PK modeling and simulation to aid in the selection of best treatment protocols and optimize dosing regimens for efficacy studies in the rat LFPI model of severe TBI.  Here we tested levetiracetam and sodium selenate. Methods: Male Sprague Dawley rats (~11-week old) were used as either naïve controls or following LFPI. Left parietal LFPI was induced using a 5mm craniotomy and injury parameters were optimized to induce moderate/severe TBI. We studied the PKs of levetiracetam and sodium selenate  after either single bolus injection (intraperitoneal (i.p.) or subcutaneous (SC)) given in either controls or LFPI rats immediately after impact (group 1) or a bolus injection followed by SC minipump placement (ALZET 2ML1) an hour after the bolus injection (group 2). The minipump was removed after 7 days. Blood was collected from the lateral tail vein at specified times between 0 and 24 hours after the bolus doses (group 1).  In group 2, blood was collected at specified times bracketing mini-pump placement and 2 hours following mini-pump removal to observe the drug washout. Right and left parietal cortical samples were also collected at similar time points. Levetiracetam concentrations were measured using validated liquid chromatography mass spectrometry (HPLC-MS/MS) methods and sodium selenate and selenium were measured using inductively coupled plasma mass spectrometry (ICP-MS) systems. A population-based PK modeling approach was utilized. Results: PK models were developed for levetiracetam and sodium selenate concentration-time profiles.  Levetiracetam and sodium selenate concentrations were well fit by one-compartment, first-order absorption PK models with and apparent clearances of 130 and 16.5 mL/hr/kg and volumes of distribution of 400 and 10 mL/kg, respectively. Brain-to-plasma ratios ranged from 0.8-1 for levetiracetam, ~1 for sodium selenate and <0.1 for selenium.    Conclusions: Obtaining PK information early in the screening process will allow us to compare drug candidates and to develop PK/PD models.  These models are used to simulate the effect of various drug doses and regimens on efficacy and safety measurements. These models will be validated in future antiepileptogenic studies post FPI, and ultimately used to inform the design of human clinical trials.   Funding: NINDS U54 NS100064