OBJECTIVES/GOALS: Allopregnanolone (ALLO), a modulator of GABAA receptors, may be useful as a treatment for human and canine benzodiazepine-refractory status epilepticus (SE). Our objective was to develop a phamacokinetic-pharmacodynamic (PKPD) model relating ALLO plasma concentrations to electroencephalographic (EEG) effects in dogs. METHODS/STUDY POPULATION: Four healthy dogs and one dog with epilepsy that had implanted intracranial electrodes were utilized. ALLO doses ranging from 1-6 mg/kg were administered IV over 5 min. EEG data were collected during four IM doses (1-2 mg/kg). Blood samples were collected up to 6 hr following dosing. ALLO concentrations were measured using HPLC-MS/MS. Power density was determined in EEG bands using a custom algorithm. A two-compartment link PKPD model was developed to describe the relation between ALLO plasma concentration and change in EEG power in the alpha, beta, delta and theta bands. RESULTS/ANTICIPATED RESULTS: ALLO caused a rapid increase in absolute power density in all EEG bands measured (1-4, >4 – 8, >8 – 12, >12 – 25, and >25 – 100 Hz). The onset of effect was rapid (1-3 min) and demonstrated by frequency band and dose analysis. Concentration-EEG data were best fit by a two-compartment PK model and sigmoidal Emax PD indirect link model. The beta frequency band was most sensitive, showing increases in power at the lowest ALLO concentrations. The EC50 concentration for the beta frequency was ~270 ng/mL. The EC50 values for effects on the other frequency bands were ~500-700 ng /mL. In conclusion, IV ALLO causes a rapid effect on EEG that can be used to determine minimal plasma concentrations associated with target engagement. DISCUSSION/SIGNIFICANCE OF IMPACT: Dose selection for future clinical trials will use the effective concentrations determined here in conjunction with studies in animal status epilepticus models. Studies are planned in client owned dogs with epilepsy to evaluate clinical efficacy in dogs and as nonclinical proof-of-concept evidence supporting translational studies in people. CONFLICT OF INTEREST DESCRIPTION: Michael Rogawski and Dorota Zolkowska are named as inventors on patent applications claiming use of neuroactive steroids including allopregnanolone and ganaxolone in the treatment of status epilepticus.

Background: Global variation in the incidence of multiple sclerosis (MS) is generally ascribed to differences in genetic and environmental risk factors. Here we investigate temporal trends in the incidence of MS and related disorders in British Columbia, Canada, from 1986 to 2010, focusing particularly on the Asian ethnic subpopulation. Methods: A longitudinal database was screened to identify newly diagnosed cases of MS and related disorders, including neuromyelitis optica and clinically isolated syndromes. Age-standardized, sex-specific mean annual incidence was calculated for the Asian and non-Asian population of British Columbia for 5-year intervals from 1986 to 2010. Temporal changes and cohort differences in incidence rates and demographic characteristics were evaluated. Results: During this period, the incidence of MS and related disorders in the non-Asian population remained relatively unchanged, from 10.41 (95% confidence interval [CI]: 9.87-10.97) to 9.91 (95% CI: 9.46-10.39) per 100,000 (p=0.167). In contrast, incidence in the Asian population doubled during the same period. This increase was driven by a precipitous rise in the incidence of MS in females from 0.71 (95% CI: 0.01-1.50) to 2.08 (95% CI: 1.43-2.91) per 100,000 (p=0.004), including both Canadian-born and immigrant Asians. The incidence of neuromyelitis optica did not change significantly during this period. Conclusions: The incidence of MS may be increasing among females in the Asian ethnic population of British Columbia.