Brexanolone

Uses

Brexanolone is a synthetic neuroactive steroid gamma-aminobutyric acid A (GABA(a)) receptor positive modulator indicated for the treatment of postpartum depression (PPD) in adult women .

Brexanolone is also used to associated treatment for these conditions: Postpartum Depression

How Brexanolone works

Brexanolone is a neuroactive steroid that occurs naturally (referred to as natural allopregnanolone) in the body when the female sex hormone progesterone is metabolized . This steroid compound is also believed to exhibit activity as a barbiturate-like, positive allosteric modulator of both synaptic and extrasynaptic GABA(a) receptors . In doing so, brexanolone can enhance the activity of GABA at such receptors by having GABA(a) receptor calcium channels open more often and for longer periods of time. Furthermore, it is believed that brexanolone elicits such action on GABA(a) receptors at a binding site that is distinct from those associated with benzodiazepines .

Concurrently, GABA is considered the principal inhibitory neurotransmitter in the human body . When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors . With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons, like those involved in neuronal pathways that may be in part responsible for eliciting certain traits of PPD like stress, anxiety, etc .

Postpartum depression (PPD) is a mood disorder that can affect women after childbirth . Women with PPD experience feelings of extreme sadness, anxiety, and exhaustion that can make it difficult or even dangerous for them to perform various daily activities or care for themselves or for others, including newborn . Although the exact pathophysiology of PPD remains unknown, it is believed that altered profiles and rapid, unpredictable fluctuations in the blood concentrations of neuroactive steroids like endogenous brexanolone (among others), GABA, and GABA receptors occur in women who are at risk of PPD after childbirth .

In particular, within the context of PPD, it is proposed that endogenous brexanolone levels can quickly drop or fluctuate variedly after childbirth and that GABA(a) receptor levels and expression are decreased and down-regulated throughout pregnancy . Such fluctuations and decreases may consequently leave women susceptible to the possibility of PPD. As a medication, synthetic brexanolone can subsequently facilitate a return of positive allosteric modulator GABA(a) modulation while GABA(a) receptor levels and expression gradually return to normal in the time following postpartum . As such, studies suggest the potential for the development of brexanolone as a new mechanism for treatment of PPD that is directly related to the underlying pathophysiology as opposed to many other antidepressant medications whose pharmacological actions are usually entirely unrelated.

Toxicity

There is limited clinical trial experience regarding human overdosage with brexanolone . In premarketing clinical studies, two cases of accidental overdosage due to infusion pump malfunction resulted in transient loss of consciousness . Both patients regained consciousness approximately 15 minutes after discontinuation of the infusion without supportive measures . After full resolution of symptoms, both patients subsequently resumed and completed treatment . Overdosage may result in excessive sedation, including loss of consciousness, and the potential for accompanying respiratory changes .

There is no available data on brexanolone use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes . However, based on findings from animal studies of other drugs that enhance GABAergic inhibition, brexanolone may cause fetal harm .

Available data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers . However, the relative infant dose (RID) is low, 1% to 2% of the maternal weight-adjusted dosage . Also, as brexanolone has low oral bioavailability in adults, infant exposure is expected to be low . There were no reports of effects of brexanolone on milk production . There are no data on the effects of brexanolone on a breastfed infant . Available data on the use of brexanolone during lactation does not suggest a significant risk of adverse reactions to breastfed infants from exposure to brexanolone . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition .

Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay .

Treatment of female and male rats with brexanolone at doses equal to and greater than 30 mg/kg/day, which is associated with 2 times the plasma levels at the maximum recommended human dose (MRHD) of 90 mcg/kg/hour, caused impairment of female and male fertility and reproduction . In female rats, brexanolone was associated with decreased mating and fertility indices, an increase in number of days to mating, prolonged/irregular estrous cycles, an increase in the number of early resorptions, and post implantation loss . Reversal of effects in females was observed following a 28-day recovery period . In male rats, brexanolone was associated with decreased mating and fertility indices, decreased conception rate, lower prostate, seminal vesicle, and epididymis weight, as well as decreased sperm numbers. Impaired female and male fertility and reproduction were not observed at 0.8 times the MRHD .

Food Interaction

• Avoid alcohol. Ingesting alcohol may increase the dizziness and drowsiness caused by brexanolone.

Brexanolone Alcohol interaction

[Moderate] GENERALLY AVOID:

Alcohol may potentiate some of the pharmacologic effects of central nervous system (CNS)-active agents.

Use in combination may result in additive CNS depression and/or impairment of judgment, thinking, and psychomotor skills.

Patients receiving CNS-active agents should be advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Brexanolone Drug Interaction

Moderate: clonazepam, desvenlafaxine, topiramateUnknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, aspirin / caffeine, sumatriptan, cholecalciferol, phytonadione

Brexanolone Disease Interaction

Major: renal impairmentModerate: depression

Volume of Distribution

The volume of distribution documented for brexanolone is approximately 3 L/kg, a value which suggests relatively extensive distribution into tissues .

Elimination Route

It has been determined that brexanolone has a low oral bioavailability of approximately Label.

Half Life

The terminal half-life observed for brexanolone is approximately 9 hours .

Clearance

The total plasma clearance determined for brexanolone is approximately 1 L/h/kg .

Elimination Route

Following the administration of radiolabeled brexanolone, it was observed that 47% of the administrated dose was recovered largely as metabolites in the feces and 42% in urine, where less than 1% as recovered as unchanged brexanolone .

Innovators Monograph

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