Abstracts

Rationale: The development of new therapies for infantile spasms, a devastating epilepsy syndrome, is hindered by the limitations of efficiently and successfully translating results from animals to humans. Our research group is working to identify new treatments for infantile spasms that have rapid onset and disease modifying effects using rodent models. The objective is to screen promising drug candidates to identify active compounds and optimize regimens that achieve rapid and sustained suppression of spasms. A component of this project is to use pharmacokinetics and pharmacodynamics to help explain the relationship between dose and exposure of efficacy studies and to determine safe and effective dosage regimens for subsequent studies. The aim of the work presented here is to characterize the pharmacokinetics and brain uptake of IL-1Ra in a rat model of infantile spasms and use this model to optimize doses and regimens for subsequent studies. Methods: Male Sprague-Dawley rat pups at post-natal (PN) day 3 were induced through a multiple-hit model to exhibit IS On PN day 4, pups received either placebo or IL-1Ra administered as single 10, 100, or 597 mg/kg intraperitoneal (i.p.) doses. Blood and samples from the right or left cerebral cortices were collected at scheduled times post-injection (plasma: 0.5, 1, 2, 4, 8, and 12 hrs; brain: 1 and 4 hrs), under isoflurane anesthesia (n=3-4 rats/group). N-acetylcysteine (150mg/kg i.p.), a drug shown by our group to have minimal brain uptake, was injected with IL-1Ra to monitor for blood contamination of brain samples. Plasma and brain IL-1Ra concentrations were measured using ELISA. Population pharmacokinetic (PK) modeling was used to characterize concentration-time profiles. Results: IL-1Ra plasma concentration-time profiles were best fit by a first-order absorption, one-compartment PK model with a 10 min lag time. Estimates for absorption rate constant, and apparent clearance and volume of distributions were 0.75 hr-1, 5 mL/hr, and 6.5 mL, respectively. IL-1Ra concentrations in brain were much lower than those in plasma with brain-to-plasma ratios less than 0.05. While brain uptake was low, IL-1Ra residence time in the brain was much greater than in plasma. This model was used to simulate doses (600 mg/kg) and regimens for repeated-dose studies. Conclusions: We have shown that IL-1Ra PK in PN day 4 male rats is linear at plasma concentrations that achieve seizure suppression. We found negligible contamination of brain IL-1ra concentrations by peripherally circulating IL-1Ra with our method of collection. We are currently exploring other routes of administration such as intracranial IL-1Ra injection to determine if alternate routes of administration result in higher and less variable brain concentrations and greater therapeutic efficacy. This model will be linked with a pharmacodynamic model to relate drug concentration and response and used to optimize dosing for future studies. This approach of integrating pharmacokinetics and pharmacodynamics earlier in the discovery and development process may reduce costs and improve success. Funding: CURE (Infantile Spasms Initiative), Department of Defense W81XWH-13-1-0180 grant, NINDS NS091170.