Find, compare & contact
Samidorphan API Manufacturers & Suppliers

General Description:

Samidorphan, identified by CAS number 852626-89-2, is a notable compound with significant therapeutic applications. is an effective atypical antipsychotic that, like other antipsychotics, is associated with weight gain, metabolic dysfunction, and increased risk of type II diabetes. Samidorphan is a novel opioid antagonist structurally related to , with a higher affinity for opioid receptors, more potent μ-opioid receptor antagonism, higher oral bioavailability, and a longer half-life, making it an attractive candidate for oral dosing. Although antipsychotic-induced weight gain is incompletely understood, it is thought that the opioid system plays a key role in feeding and metabolism, such that opioid antagonism may be expected to ameliorate these negative effects. Samidorphan has been shown in animal models and clinical trials to ameliorate -induced weight gain and metabolic dysfunction. Samidorphan was first approved as a variety of fixed-dose combination tablets with by the FDA on May 28, 2021, and is currently marketed under the trademark LYBALVI™ by Alkermes Inc.

Indications:

This drug is primarily indicated for: Samidorphan is indicated in combination with for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia in adults. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Samidorphan undergoes metabolic processing primarily in: Samidorphan is primarily metabolized by CYP3A4, with minor contributions from CYP3A5, CYP2C19, and CYP2C8. The main metabolism products are RDC-9986 (an N-dealkylated metabolite) and RDC-1066 (an N-oxide metabolite); although both metabolites have a nanomolar affinity for the μ-, κ-, and δ-opioid receptors, neither is thought to contribute to the pharmacological effects of samidorphan. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Samidorphan are crucial for its therapeutic efficacy: Samidorphan pharmacokinetics are linear over the range of clinically relevant concentrations, and steady-state kinetics are reached by seven days with once-daily oral administration. Upon reaching steady-state, with a once-daily dose of 10 mg samidorphan combined with 20 mg , samidorphan has a mean C_max of 45.1 ± 11.4 ng/mL and an AUC_24h of 364 ± 112 ng\*h/mL. Samidorphan has an absolute oral bioavailability of 69% and a T_max of 1-2 hours. Samidorphan pharmacokinetics are not significantly impacted by food; following a high-fat meal, the C_max was 0.85 (90% CI 0.76, 0.94) and the AUC 1.03 (90% CI 1.0, 1.05) that for the fasted state. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Samidorphan is an important consideration for its dosing schedule: Samidorphan has a mean half-life of 7-11 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Samidorphan exhibits a strong affinity for binding with plasma proteins: Samidorphan is between 23 and 33 percent bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Samidorphan from the body primarily occurs through: Samidorphan is primarily renally excreted, with 67% of unchanged parent and metabolites eliminated in urine and another 16% in feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Samidorphan is distributed throughout the body with a volume of distribution of: Samidorphan following a single 10 mg oral dose had an apparent volume of distribution between 336.59 ± 75.42 and 557.6 ± 120.51 L, depending on age, gender, and concomitant food consumption. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Samidorphan is a critical factor in determining its safe and effective dosage: Samidorphan has a mean clearance of 35-45 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Samidorphan exerts its therapeutic effects through: Samidorphan, a novel opioid-system modulator, functions primarily as a μ-opioid receptor antagonist and as a κ/δ-opioid receptor partial agonist _in vitro_ with an overall profile consistent with a μ-opioid receptor antagonist _in vivo_ and is currently used to counteract -induced adverse effects of weight gain and metabolic dysfunction. Samidorphin generally has a mild side effect profile. As an opioid antagonist, it can potentiate opioid withdrawal in dependent patients; it should not be administered within seven days from the last use of short-acting opioids and at least 14 days after cessation of long-acting opioids. Similarly, samidorphan use may lead to life-threatening opioid overdose, either in patients who attempt to overcome the samidorphan-induced opioid blockade or resume opioid use when therapy is interrupted or discontinued. Several other effects may be noted in combination with , including increased risk for potentially fatal cerebrovascular events in elderly patients with dementia-related psychosis, neuroleptic malignant syndrome, hyperprolactinemia, and tardive dyskinesia. is associated with an increased risk of metabolic dysfunction, including hyperglycemia, type II diabetes, dyslipidemia, and weight gain. Patients may be at increased risk for orthostatic hypotension and syncope, particularly in patients with known cardiovascular/cerebrovascular disease. Leukopenia, neutropenia, and agranulocytosis may occur and should be monitored for; patients with a history of seizure should also be monitored. This combination may exhibit anticholinergic (antimuscarinic) effects. It should be used with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus, or related conditions. Serious allergic reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Patients may be at increased risk of cognitive and motor impairment; caution while operating machinery is recommended. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Samidorphan functions by: Samidorphan is a novel analogue containing a 3-carboxamido group that functions as an opioid receptor modulator, both _in vitro_ and _in vivo_. Numerous _in vitro_ studies have demonstrated that samidorphan binds with high affinity to the μ-, κ-, and δ-opioid receptors with K_i values of 0.052 ± 0.0044, 0.23 ± 0.018, and 2.7 ± 0.36 nM, respectively. Samidorphan acts as an antagonist at the μ-opioid receptor when it signals through G_αi proteins, a partial agonist when the receptor signals through G_αoA, G_αoB, and G_αz proteins, and essentially lacks β-arrestin-mediated signalling; samidorphan also acts as a partial agonist at both the κ- and δ-opioid receptors _in vitro_. In addition, both the major N-dealkylated and the major N-oxide human metabolites bind to the μ-, κ-, and δ-opioid receptors (K_i values of 0.26, 23, and 56, and 8, 110, and 280 nM, respectively); the former functions as a μ-opioid receptor agonist and the latter as an antagonist. Overall, samidorphan functions primarily as a μ-opioid antagonist _in vivo_. is an efficacious antipsychotic whose use is limited, in part, by known adverse effects mediated through metabolic dysfunction: hyperglycemia/diabetes mellitus, hyperlipidemia, and weight gain. The exact mechanisms behind this metabolic dysfunction are incompletely understood, but it is known that opioid signalling is involved in feeding and metabolism. Clinical studies have demonstrated that the addition of samidorphan to helps mitigate its metabolic-related adverse effects; presumably, this is due to opioid receptor signalling, though the exact mechanism remains to be determined. The appropriateness of samidorphan in combination therapy is due in part to its relatively mild side effect profile and low abuse potential. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Samidorphan belongs to the class of organic compounds known as phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene, classified under the direct parent group Phenanthrenes and derivatives. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Phenanthrenes and derivatives class, specifically within the None subclass.

Categories:

Samidorphan is categorized under the following therapeutic classes: Alkaloids, Central Nervous System Agents, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, Morphinans, Opiate Alkaloids, Opioid Antagonists, Peripheral Nervous System Agents, Phenanthrenes, Sensory System Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Samidorphan include:

• Water Solubility: freely soluble
• Melting Point: 196.6-196.8
• pKa: 8.3, 10.1