Esketamine API Manufacturers

General Description:

Esketamine, identified by CAS number 33643-46-8, is a notable compound with significant therapeutic applications. Major depressive disorder (MDD) is a significant cause of disability worldwide and the most common illness preceding suicide. On March 5, 2019, the nasal spray drug, _esketamine_, also known as _Spravato_ (by Janssen Pharmaceuticals), was approved by the FDA for treatment-resistant major depression. Esketamine is the s-enantiomer of . Ketamine is a mixture of two enantiomers (mirror image molecules). This is the first time that the FDA has approved esketamine for any use. The FDA approved ketamine (Ketalar) in 1970. Esketamine may prove to be a promising treatment for patients diagnosed with major depressive disorder who have not experienced an improvement in symptoms despite treatment with various medications and therapies. The intranasal route of administration for this drug allows for easy administration and a fast onset of action, which sets it apart from many other antidepressant agents that may take several weeks to take effect.

Indications:

This drug is primarily indicated for: Esketamine is indicated in combination with an oral antidepressant for the treatment of treatment-resistant depression in adults. It is also indicated for the treatment of depressive symptoms in adults with major depressive disorder experiencing acute suicidal ideation or behaviour. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Esketamine undergoes metabolic processing primarily in: Esketamine is mainly metabolized to the _noresketamine_ metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19. Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Esketamine are crucial for its therapeutic efficacy: Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Esketamine is an important consideration for its dosing schedule: The mean terminal half-life (t1/2) ranges from 7 to 12 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Esketamine exhibits a strong affinity for binding with plasma proteins: The protein binding of esketamine is about 43% to 45%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Esketamine from the body primarily occurs through: Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Esketamine is distributed throughout the body with a volume of distribution of: The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Esketamine is a critical factor in determining its safe and effective dosage: The average clearance of esketamine is approximately 89 L/hour following intravenous administration. Elimination of the major esketamine metabolite, _noresketamine_, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Esketamine exerts its therapeutic effects through: General effects Esketamine is considered a central nervous system (CNS) depressant agent. It may cause sedation, dizziness, and lethargy, among other symptoms. This drug has dissociative and antidepressant properties. Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills. Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive. The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion. Effects on cardiac electrophysiology The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers. A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine. Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine. Effects on blood pressure Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses. Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours. Cognitive effects In a study of healthy volunteers, one dose of this agent caused decline in cognitive performance 40 minutes after administration. Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration. Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration. Reports of long-term memory or cognitive impairment have been made following repeated ketamine misuse or abuse. No adverse effects of esketamine nasal spray on cognitive function were seen in a one-year open-label safety study. The long-term cognitive effects of esketamine have not been studied for more than a 1 year period, therefore, the risk of cognitive decline with long-term use is not yet confirmed. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Esketamine functions by: Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The exact mechanism by which esketamine acts as an antidepressant is unknown. The primary circulating metabolite of esketamine (_noresketamine_) shows activity at the same receptor with a weaker affinity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Esketamine belongs to the class of organic compounds known as chlorobenzenes. These are compounds containing one or more chlorine atoms attached to a benzene moiety, classified under the direct parent group Chlorobenzenes. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the Halobenzenes subclass.

Categories:

Esketamine is categorized under the following therapeutic classes: Agents producing tachycardia, Anesthetics, Anesthetics, General, Antidepressive Agents, Antidepressive Agents Indicated for Depression, Central Nervous System Agents, Central Nervous System Depressants, Cyclohexanes, Cycloparaffins, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (weak), Cytochrome P-450 CYP2B6 Substrates, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Substrates, Miscellaneous Antidepressants, Nervous System, NMDA Receptor Antagonists, Non-Competitive N-Methyl D-Aspartate (NMDA) Receptor Antagonists, Psychoanaleptics, Psychotropic Drugs. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Esketamine include:

• Water Solubility: Freely soluble in water
• Melting Point: 92.5
• Boiling Point: 363.8ºC at 760mmHg
• logP: 3.28870
• pKa: 7.5