Abstracts

Rationale: Project 2 of EpiBioS4Rx aims to identify new therapies to prevent post-traumatic epilepsy (PTE) following traumatic brain injury (TBI). The EpiBioS4Rx project 2 utilizes a multicenter preclinical therapy screening platform which includes pharmacokinetic (PK) and pharmacodynamic (PD) studies early in the preclinical screening process to determine brain penetration and optimize treatment delivery. The drugs’ pharmacokinetics and brain uptake are characterized in both naïve animals and in a lateral fluid percussion injury (LFPI) rat model of TBI.The objective of this work is to compare the pharmacokinetics and brain uptake of Kineret (IL-1ra, interleukin 1 receptor antagonist), deferiprone (iron chelator), and Z944 (T-calcium channel blocker). These drugs encompass a range of physiochemical properties and mechanisms of action. These results will also be compared with those from previous studies with levetiracetam and sodium selenate. Methods: Male 11- week old Sprague Dawley rats were used as either naïve controls or following LFPI induction at the left parietal region, using a 5mm craniotomy and injury parameters optimized to induce severe TBI with a mortality of ~30%. Rats received either a bolus injection (intraperitoneal or subcutaneous), which in LFPI rats was given immediately after injury. Blood was collected from the lateral tail vein at specified timepoints bracketing 0 and 24 hours after the bolus. Parietal cortical samples were collected at similar timepoints. Deferiprone, and Z944 concentrations in plasma and brain were measured using validated high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) methods. Human IL-1ra was measured using an enzyme-linked immunosorbent assay. Non-compartmental analysis and compartmental PK modeling was completed. Results: All drugs exhibited relatively rapid absorption with maximum drug concentrations achieved at 0.5hr for deferiprone and Z944 and 1 hr for Kineret. Elimination half-lives ranged from 1-5 hrs with Kineret exhibiting the slowest elimination. Z944 exhibited good brain uptake with brain-to-plasma ratios ranging from 0.7-1. Kineret has very poor brain penetration with brain-to-plasma ratios <0.001 which may limit efficacy. While drug exposures were similar in the naïve and injured animals, the drug concentrations in the left (injured) cortex were greater than the right cortex in LFPI rats. Conclusions: The diverse physiochemical properties of the drugs screened resulted in a range of absorption, elimination, and brain penetrations. Obtaining PK information early in the screening allows us to better identify optimal compounds and assist with formulation development and dosing protocols. We can also develop PK/PD models to simulate the effect of drugs on efficacy and safety measurements, guiding optimal treatment protocols in EpiBioS4Rx. Funding: NINDS U54 NS100064 (EpiBioS4Rx)