Pharmacokinetics of SAGE-547 in patients with super refractory status epilepticus

Objective: This open-label, phase 1/2 study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of SAGE-547 Injection, a proprietary formulation of the endogenous neuroactive steroid allopregnanolone, in super-refractory status epilepticus (SRSE) patients. Background: SRSE is a life-threatening condition characterized by status epilepticus (SE) resistant to first-, second- , and third-line therapy. Allopregnanolone is a potent positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and has shown anticonvulsive activity in a variety of pre-clinical models, including pharmaco- resistant seizure models. SAGE-547 Injection is a stable and aqueous formulation of allopregnanolone for intravenous injection that is under investigation for the treatment of SRSE. Design/Methods: A 5-day continuous intravenous infusion of SAGE-547 Injection was administered to 25 patients with SRSE and receiving third line anesthetic agents (TLA) for seizures or burst suppression treatment. Participants were administered either a standard dose regimen (n=19) or a high dose regimen (n=6) and were subsequently subjected to attempts to wean off all TLAs. A model was used to select a standard dose that resulted in a mean plasma exposure comparable to the highest endogenous concentrations observed during the third trimester of pregnancy (∼157nM), which is tolerated by women without apparent adverse effects. Results: The standard SAGE-547 Injection dose regimen yielded a mean (SD) steady-state concentration of 66.2 (21.93) ng/mL, whereas the high dose regimen yielded a mean (SD) steady state concentration of 113.6 (42.08) ng/mL. The steady-state concentrations of allopregnanolone were nearly dose proportional in both the standard and high dose regimens. Therefore, clearance (mean (SD) of 1.36 (0.56) L/h/kg) was independent of dose. The half-life and volume of distribution could not be determined due to insufficient sampling after the cessation of infusion. Conclusions: Standard and high dosing of SAGE-547 Injection resulted in plasma concentrations in line with target exposures, and clearance was not dose dependent.