3α-Hydroxy-5α-pregnan-20-one

318.49

318.49

S39XZ5QV8Y

2400

37.3

4.89

white

1.1±0.1 g/cm3

177 °C

431.2±18.0 °C at 760 mmHg

183.9±13.8 °C

1.524

chloroform: 20 mg/mL, clear, colorless

Store at RT

D +87.7° (abs alc)

NONH for all modes of transport

3

22-24/25

TU4383000

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.

In premarketing studies, liver test abnormalities were uncommon in patients receiving brexanolone (

The plasma protein binding recorded for brexanolone is greater than 99% and was determined to be independent of plasma concentrations.

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.|FDA Label|Treatment of postpartum depression

Brexanolone is a unique, intravenously administered, neuroactive steroidal antidepressant used in the therapy of moderate-to-severe postpartum depression. In prelicensure clinical trials, brexanolone therapy was not associated with an increased rate of serum aminotransferase elevations, and it has not been linked to instances of clinically apparent acute liver injury.

Antidepressant Agents

Brexanolone potentiated GABA-mediated currents from recombinant human GABA(a) receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits. Moreover, it was determined during a Phase 1 randomized, placebo and positive-controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects that brexanolone use did not prolong the QT interval to any clinically relevant extent when administered at 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour).

Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general ANESTHESIA, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. (See all compounds classified as Anesthetics.)

It has been determined that brexanolone has a low oral bioavailability of approximately <5% in adults, which suggests infant exposure would also be expected to be low.|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.|The volume of distribution documented for brexanolone is approximately 3 L/kg, a value which suggests relatively extensive distribution into tissues.|The total plasma clearance determined for brexanolone is approximately 1 L/h/kg.

Brexanolone is extensively metabolized by non-cytochrome (CYP) based pathways by way of three main routes - keto-reduction (via aldo-keto reductases), glucuronidation (via UDP-glucuronosyltransferases), and sulfation (via sulfotransferases). Three predominant circulating metabolites result from such metabolic pathways and they are all pharmacologically inactive and ultimately do not contribute to the overall efficacy of the medication.

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

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.

3 alpha Hydroxy 5 alpha pregnan 20 one

Brexanolone|Allopregnanolone|2400|Schedule IV - Substances in the DEA Schedule IV have a low potential for abuse relative to substances in Schedule III.|No

Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients