Brexanolone as adjunctive therapy in super‐refractory status epilepticus

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Excerpt

Status epilepticus (SE) is a life‐threatening condition that involves persistent or recurring seizures.1 Patients with recurrent seizures after first‐line emergency treatment are commonly administered second‐line antiepileptic drugs (AEDs).2 Patients who fail to respond to second‐line agents are said to have refractory SE (RSE) and are commonly administered continuous intravenous (IV) anesthetic third‐line agents (TLAs).2 Super‐refractory status epilepticus (SRSE) is a life‐threatening form of status epilepticus that continues or recurs despite 24 hours or more of TLA treatment.2 Experimental evidence supports that SE becomes more refractory with time,3 and achieving resolution of seizures and return of consciousness takes longer with SRSE than with RSE or SE.4
A major concern for current treatments is the lack of clinical evidence for treatment outcomes.5 Between 26.6% and 36.6% of patients with SE fail to respond to the administration of first‐line agents,7 of which approximately 23% also fail second‐line agents9 and 10% to 15% fail TLAs,10 thus progressing to SRSE. Approximately one third of patients with RSE or SRSE die,2 one third recover, typically with neurological or other deficits, and one third return to baseline.2 A retrospective study revealed that 76.2% of discharged patients with an in‐hospital diagnosis of RSE had a poor functional outcome as defined by modified Rankin score.11
Allopregnanolone is a potent, endogenously produced neuroactive steroid that acts as a positive allosteric modulator (PAM) on a broad range of γ‐aminobutyric acid type A receptor (GABAAR) isoforms12 expressed throughout the brain, including those that mediate either phasic or tonic inhibition.17 Extrasynaptic receptors containing the δ‐subunit that mediate tonic inhibition are particularly sensitive to modulation by neurosteroids.18 The robust effects of allopregnanolone on multiple GABAA receptor populations in vitro produces a potent regulation of cortical function, especially under conditions of hyperexcitability.20
Allopregnanolone has demonstrated significant protection against seizures in several animal models.15 Continuous allopregnanolone IV administration in two murine seizure models predict that anticonvulsant effects should occur at plasma concentrations within the range of 37 to 142ng/ml.22 Short infusions of allopregnanolone that result in plasma concentrations that range from 9.4 to 25.1μg/ml (30 and 80μM) for up to 90 minutes have been previously reported to cause anesthesia in rats, without notable heart or respiratory rate effects.22
In addition to the preclinical evidence, three recent case studies report the successful treatment of SRSE with brexanolone (USAN; formerly SAGE‐547 Injection; Sage Therapeutics, Inc., Cambridge, MA), a proprietary formulation of allopregnanolone, in human patients.25 Given the evidence suggesting potential benefits of allopregnanolone in treating SRSE, the objectives of the present study were to evaluate the safety and tolerability, pharmacokinetics (PK), and response to brexanolone in a cohort of patients with SRSE.
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