Oliceridine API Manufacturers

General Description:

Oliceridine, identified by CAS number 1401028-24-7, is a notable compound with significant therapeutic applications. Severe acute pain occurs through nociceptive signalling involving both ascending and descending spinal pathways, in which nerve conductance is mediated in part by the action of opioid receptors. Opioid receptors are seven-transmembrane G-protein-coupled receptors (GPCRs), of which the μ-opioid receptor subtype is predominantly targeted by and is responsible for the effects of opioid agonists. However, due to the ability of some opioid agonists to bind to other targets, as well as activation of additional downstream pathways from opioid receptors such as those involving β-arrestin, the beneficial analgesic effects of opioids are coupled with severe adverse effects such as constipation and respiratory depression. Oliceridine (formerly known as TRV130) is a "biased agonist" at the μ-opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of β-arrestin. By acting as a biased agonist, oliceridine provides comparable analgesia compared with traditional opioids such as at a comparable or decreased risk of opioid-related adverse effects such as constipation and respiratory depression. Oliceridine was first reported in 2013, but was initially not approved by the FDA due to concerns raised by the Anesthetic and Analgesic Drug Products Advisory Committee. Oliceridine gained FDA approval on August 7, 2020, and is currently marketed by Trevena Inc as OLINVYK™.

Indications:

This drug is primarily indicated for: Oliceridine is indicated for the management of acute pain in adults severe enough to require intravenous opioid analgesics and for whom no acceptable alternative treatments exist. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Oliceridine undergoes metabolic processing primarily in: Oliceridine is primarily metabolized hepatically by CYP3A4 and CYP2D6 _in vitro_, with minor contributions from CYP2C9 and CYP2C19. None of oliceridine's metabolites are known to be active. Metabolic pathways include N-dealkylation, glucuronidation, and dehydrogenation. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Oliceridine are crucial for its therapeutic efficacy: Oliceridine administered as a single intravenous injection of 1.5, 3, or 4.5 mg in healthy male volunteers had a corresponding C_max of 47, 76, and 119 ng/mL and a corresponding AUC_0-24 of 43, 82, and 122 ng\*h/mL. Simulations of single doses of oliceridine between 1-3 mg suggest that the expected median C_max is between 43 and 130 ng/mL while the expected median AUC is between 22 and 70 ng\*h/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Oliceridine is an important consideration for its dosing schedule: Oliceridine has a half-life of 1.3-3 hours while its metabolites, none of which are known to be active, have a substantially longer half-life of 44 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Oliceridine exhibits a strong affinity for binding with plasma proteins: Oliceridine is approximately 77% 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 Oliceridine from the body primarily occurs through: Approximately 70% of oliceridine is eliminated via the renal route, of which only 0.97-6.75% of an initial dose is recovered unchanged. The remaining 30% is eliminated in feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Oliceridine is distributed throughout the body with a volume of distribution of: Oliceridine has a mean steady-state volume of distribution of 90-120 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Oliceridine is a critical factor in determining its safe and effective dosage: Healthy volunteers given doses of oliceridine between 0.15 and 7 mg had mean clearance rates between 34 and 59.6 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Oliceridine exerts its therapeutic effects through: Oliceridine is a biased μ-opioid receptor agonist that acts through downstream signalling pathways to exert antinociceptive analgesia in patients experience severe acute pain. Results from multiple clinical studies and simulation data demonstrate that oliceridine exerts significant analgesic benefits within 5-20 minutes following administration but dissipates quickly with a half-life between one and three hours. Despite an improved adverse effect profile over conventional opioids, oliceridine carries important clinical warnings. Oliceridine has the potential to cause severe respiratory depression, especially in patients who are elderly, cachectic, debilitated, or who otherwise have chronically impaired pulmonary function. In addition, severe respiratory depression or sedation may occur in patients with increased intracranial pressure, head injury, brain tumour, or impaired consciousness. Patients with adrenal insufficiency or severe hypotension may require treatment alterations or discontinuation. Finally, oliceridine has been demonstrated to prolong the QTc interval and has not been properly evaluated beyond a maximum daily dose of 27 mg; it is recommended not to exceed 27 mg per day. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Oliceridine functions by: Pain perception follows a complex pathway initiated in primary sensory neurons, subsequently transmitted to the spinal cord dorsal horn and through ascending axons to multiple regions within the thalamus, brainstem, and midbrain, and finally relayed through descending signals that either inhibit or facilitate the nociceptive signalling. Opioid receptors are seven-transmembrane G-protein-coupled receptors (GPCRs) that can be divided into μ, κ, δ, and opioid-like-1 (ORL1) subtypes,. However, the μ-opioid receptor is predominantly targeted by and is responsible for the effects of traditional opioids. GPCRs in the inactive state are bound intracellularly by a complex consisting of a G_α, β, and γ subunit together with guanosine diphosphate (GDP). Activation of the GPCR through extracellular agonist binding catalyzes the replacement of GDP with guanosine triphosphate (GTP), dissociation of both G_α-GTP and a βγ heterodimer, and subsequent downstream effects. In the case of the μ-opioid receptor, the G_α-GTP directly interacts with the potassium channel K_ir3 while the dissociated Gβγ subunit directly binds to and occludes the pore of P/Q-, N-, and L-type Ca²⁺ channels. Furthermore, opioid receptor activation inhibits adenylyl cyclase, which in turn reduces cAMP-dependent Ca²⁺ influx. By altering membrane ion conductivity, these effects modulate nociceptive signalling and produce an analgesic effect. In addition to the G-protein pathway, μ-opioid receptor activation can also result in downstream signalling through β-arrestin, which results in receptor internalization and is associated with negative effects of opioid use including respiratory depression, gastrointestinal effects, and desensitization/tolerance. Oliceridine acts as a "biased agonist" at the μ-opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of β-arrestin. Competetive binding assays and structural modelling suggest that the binding site for oliceridine on the μ-opioid receptor is the same as for classical opioids. However, molecular modelling supports a model whereby oliceridine binding induces a different intracellular conformation of the μ-opioid receptor, specifically due to a lack of coupling with transmembrane helix six, which confers the specificity for G-protein over β-arrestin interaction. Numerous _in vitro_, _in vivo_, and clinical studies support the view that this biased agonism results in comparable analgesia compared with traditional opioids at a comparable or decreased risk of opioid-related adverse effects such as constipation and respiratory depression. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Oliceridine is categorized under the following therapeutic classes: Analgesics, Anesthetics, Central Nervous System Agents, Central Nervous System Depressants, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Ligands, Narcotics, Nervous System, Neuraxial Anesthetics, Opiate Agonists, Opioid Agonist, Opioids, Peripheral Nervous System Agents, Sensory System Agents, Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Oliceridine include:

• logP: 3.19