Brexanolone

Mechanism of Action

The mechanism of action of brexanolone is not fully known. Brexanolone is an aqueous formulation of allopregnanolone. Allopregnanolone is a major metabolite of progesterone. Levels of allopregnanolone continue to rise with progesterone during pregnancy, with the highest in the third trimester.[6] Allopregnanolone is a potent, endogenous neuroactive steroid that modulates neuronal excitability through positive allosteric modulation on the synaptic and extrasynaptic gamma-aminobutyric acid (GABA) type A receptors.[7] The extrasynaptic GABA type A receptors mediate tonic inhibition which makes allopregnanolone’s mechanism unique compared to benzodiazepines which mediate the phasic inhibition at GABA type A receptors.[8]

Administration

Brexanolone is only available through a restricted program called the Risk Evaluation and Mitigation Strategy Program. This program requires brexanolone to be administered intravenously at a certified health care facility under the close supervision of a health care provider. Patients are required to enroll in this program before drug administration. Brexanolone is administered as a continuous IV infusion over a period of 60 hours, for approximately 2.5 days.

The prescribed dosing regimen is as follows:

• 0 to 4 hours: Start with a dose of 30 mcg/kg/hour
• 4 to 24 hours: Increase the dose to 60 mcg/kg/hour
• 24 to 52 hours: Increase the dose to 90 mcg/kg/hour
• 52 to 56 hours: Decrease the dose to 60 mcg/kg/hour
• 56 to 60 hours: Decrease the dose to 30 mcg/kg/hour

If the patient does not tolerate the dose of 90 mcg/kg/hour, dose reduction to 60 mcg/kg/hour is the recommendation. Brexanolone is available as 100mg/20ml single-dose vials and requires dilution before administration.

Brexanolone exhibits dose-proportional pharmacokinetics over a dose range of 30 mcg/kg/hour to 270mg/kg/hour. After administration, brexanolone is extensively bound to plasma proteins, approximately 99%, and has an elimination half-life of 9 hours. Brexanolone has a volume of distribution of  3L/kg, suggesting extensive distribution in tissues. Brexanolone is metabolized by extra-hepatic, non-CYP pathways mainly through keto-reduction, glucuronidation, and sulfation; therefore, no dosage adjustment is necessary with hepatic impairment. Excretion is mostly in feces and urine, approximately 47% and 42%, respectively, with the remaining 1% as unchanged brexanolone. The FDA prohibits the usage of brexanolone in patients who have an eGFR of less than 15 mL/minute/1.73 m^2 due to the possible accumulation of solubilizing agent, betadex sulfobutyl ether sodium, in brexanolone. 

Brexanolone transfers to breastmilk; however, the relative infant exposure to the drug is considered low. A concentration of less than 10ng/ml of brexanolone was present in breast milk 36 hours after the completion of infusion, suggesting the maximum relative infant dose for brexanolone during the infusion was 1% to 2%.

Adverse Effects

Clinical trials have demonstrated brexanolone as generally well tolerated. The most common adverse effects associated with brexanolone are dizziness, sedation/somnolence, xerostomia, loss of consciousness, and hot flushes.[9][10]

In patients whose symptoms of postpartum depression worsen or develop suicidal ideation or behavior, providers should consider changing the therapeutic regimen or stopping brexanolone completely. 

At the highest recommended infusion rate of 90 mcg/kg/hour, brexanolone causes a minimal increase in the QTc interval.

Contraindications

No known contraindications are in the manufacturer’s labeling for brexanolone.

Monitoring

Continuous monitoring is necessary as brexanolone can cause excessive sedation and sudden loss of consciousness. Because of this, brexanolone is only available through the restricted distribution program. During infusion, patients need continuous monitoring with pulse oximetry and must be accompanied at all times by staff or family members while interacting with their children. 

If patients experience hypoxia, infusion needs to be stopped immediately and should not be resumed. The FDA has cautioned providers to monitor patients every 2 hours for sedative effects during non-sleep periods. In the case of excessive sedation or sudden loss of consciousness, dose interruption is recommended. Patients regain consciousness within 15 to 60 minutes of dose interruption.[10] After recovery, infusion may be resumed at the same or lower dose as determined by the health care provider.

Patients are prohibited from driving or operating machinery until the sedative effects of the drug have entirely resolved.

Patients require close monitoring for worsening depression and suicidal thoughts or behaviors. In such cases, it is recommended to change the dosing regimen or discontinue brexanolone altogether. Concomitant use with central nervous system(CNS) depressants such benzodiazepines, alcohol, opioids, and antidepressants also requires close monitoring and/or avoidance of these agents.

Toxicity

Brexanolone has a rapid onset of action within 60 hours of infusion and has a sustained response for up to 30 days after infusion. Patients in clinical trials were not followed after a 30 day follow-up period, limiting data on toxicity from long-term use. Long term efficacy of brexanolone, when compared with other antidepressants, is unknown and needs further research.[10]

Limited clinical trial data is available concerning overdose. The manufacturer's labeling describes two cases of accidental overdose. These were due to infusion pump malfunction resulting in the sudden loss of consciousness. Patients recovered after 15 minutes of discontinuation without the need for supportive measures. The infusion was resumed, and patients completed treatment. It is recommended to stop the infusion immediately in case of overdose and initiate supportive measures as needed. 

Clinical studies on exogenous allopregnanolone administration have reported sedation, intoxication, flushing, and headaches; however, there are no reports of severe adverse events.[11][12][13]

Enhancing Healthcare Team Outcomes

Postpartum depression presents as one of the most common complications after childbirth and can be a significant cause of suffering for the mother, infant, siblings, and family.[3] In the USA, the estimated prevalence of postpartum depression varies in states ranging from 8 to 20%, with an overall mean prevalence of 11.5%. Postpartum depression affects at a multifactorial level resulting in maternal suicide, inability to work, child morbidity associated with impaired mother-infant bonding, and malnutrition within the first year of life.[4][14][15] The long-term consequence of this disruptive parenting results in multiple adverse child outcomes, including increased risk for behavioral problems, lower mathematics grades, and development of depression.[16] Therefore screening and early treatment for postpartum depression are essential. Many women treated with selective serotonin reuptake inhibitors (SSRIs) for postpartum depression do not achieve adequate response or full remission of depressive symptoms.[17][18] Therefore, an urgent need for therapy specifically designed for postpartum depression was needed.

Several studies have demonstrated the peripartum fluctuations in reproductive hormones; most importantly, allopregnanolone (the primary progesterone metabolite) play a pivotal role in the etiology of postpartum depression.[19] Allopregnanolone is a potent positive allosteric modulator at the synaptic and extrasynaptic GABA type A receptors. Postulates are that the sudden decrease in the allopregnanolone levels after childbirth prevents the GABA type A receptors from adaptation, resulting in postpartum depression.[20]

Since allopregnanolone has poor aqueous solubility, oral bioavailability, and rapidly metabolized, an aqueous intravenous formulation, brexanolone, a proprietary of allopregnanolone, has been in development for the treatment of postpartum depression. To this date, one phase 2 and two phase 3 randomized, double-blind placebo-controlled trials have been conducted, showing promising results of brexanolone in the treatment of postpartum depression. All clinical trials showed a substantial reduction in the Hamilton Rating Scale for Depression [HAM-D] at 60 hours compared with the placebo; there was a rapid onset of action and sustained response during the treatment period with brexanolone.[9][10] Rapid onset of action is essential as when postpartum patients receive treatment with SSRIs, it takes 4 to 6 weeks to achieve an adequate antidepressant response.[21] Furthermore, the prompt onset of action determines the likelihood of near-term recovery and full remission of symptoms.[22]

The most common adverse effects in phase 3 trials were headache, dizziness, and somnolence; therefore, close monitoring is required during infusion treatment with brexanolone. Although the incidence of dizziness and somnolence were higher in the brexanolone treatment group, the events were typically mild and did not require discontinuation of treatment.[9][10] As of this writing, an ongoing phase 3 randomized, double-blind placebo-controlled trial is evaluating the efficacy and safety of brexanolone in adolescent females (15 to 17 years of age) with postpartum depression. 

Although these trials showed promising results, there are few limitations. The generalizability of brexanolone to the wider population is yet to be determined as the trials have focused on women with moderate to severe postpartum depression. No data exists on the effects of brexanolone after the completion of a 30-day follow-up period.[10] The need for a 60-hour intravenous infusion may be problematic for some patients because of logistic reasons.  It would be interesting to see if an oral formulation of brexanolone with a similar efficacy is formulated or developed in the future.[23]

Despite these limitations, brexanolone is the first therapeutic drug to be approved by the FDA, specifically for the treatment of postpartum depression. More large-scale clinical trials are needed to determine the long-term safety and efficacy of brexanolone in the treatment of postpartum depression.

Administration of brexanolone requires the effort of an interprofessional team consisting of physicians, specialists, specialty-trained nurses, and pharmacists, communicating and collaborating to bring about the optimal therapeutic results in these cases. Pharmacy needs to verify the dosing and administration schedule and check for potential drug-drug interactions and let nursing know if any red flags are present. Nursing will administer the medication and must watch for signs of intolerance or adverse reactions as the dose titrates upward, and inform the ordering clinician if they notice any issues so that therapy can be discontinued or modified. Only through this type of interprofessional teamwork can brexanolone be effective in treating postpartum depression. [Level 5]