Abstracts

Rationale: Allopregnanolone (ALLO), a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has physico-chemical and pharmacological properties that suggest it may be useful as a first-line treatment for human and canine status epilepticus (SE). To evaluate our hypothesis, we completed an IV and IM ALLO pharmacokinetic-pharmacodynamic (PKPD) study in dogs. The primary objective was to build a PKPD model relating plasma ALLO concentrations to electroencephalographic (EEG) activity. Methods: Four healthy dogs and one with epilepsy and implanted intracranial electrodes were used. ALLO doses ranging from 1-6 mg/kg were given IV over 5 minutes in five dogs or IM in two dogs. EEG data were collected during four IV and both IM doses (1-2 mg/kg). Blood samples were collected up to 6 hrs post-dose. ALLO concentrations were measured by a UPLC-MS/MS system. PKPD modeling and simulation were performed using Phoenix NLME (version 8.0). EEG were analyzed using Matlab (version 2018b). A PK model was developed to describe IV administration. Thereafter, PK parameter estimates were fixed and indirect-link Emax PD models were evaluated. Results: ALLO exhibits dose-proportional, two-compartment PK at the doses studied (V1: 0.7 L/kg, V2: 12.9 L/kg, CL1: 6.4 L/hr/kg, CL2: 5.0 L/hr/kg, IM absorption rate constant: 2.1 1/hr, IM bioavailability: 65-100%). Concentration-EEG data were best fit by sigmoidal Emax models (ke0: 0.1-1.85 1/min, EC50: 102-722 ng/mL). The effect was rapid (ke0 half-life of 22-40 seconds) across all frequency bands following IV administration. The beta frequency band showed an increase in absolute power density at the lowest concentrations compared to the others, suggesting that the beta frequency band may be most sensitive to plasma ALLO concentrations. The relative power density of the beta frequency band decreased following IV ALLO administration. None of these effects were observed following IM injection. Although the overall exposures were similar following IV and IM injections, the EEG changes appear to be driven by the drug concentration not total exposure. Conclusions: In conclusion, IV ALLO results in rapid EEG changes. The beta frequency band may serve as a surrogate marker translatable to clinical studies to assess whether ALLO has reached the brain. The modulation in beta frequency band relative power density is consistent with previously reported EEG changes associated with benzodiazepines, suggesting a differential effect on global neuronal excitability. Finally, although the IM route exhibits a longer terminal half-life which may be advantageous for the treatment of SE, a formulation that enables faster absorption and attainment of higher concentrations is necessary to further the development of ALLO for IM use. Additional research is necessary to evaluate the clinical significance of these findings. Funding: AES Pre-Doctoral Fellowship 2017-2018AFPE Pre-Doctoral Fellowship 2017-2018, 2018-2019MacMillan Epilepsy Innovation Fund