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General Description:

Aripiprazole lauroxil, identified by CAS number 1259305-29-7, is a notable compound with significant therapeutic applications. Aripiprazole lauroxil is a long-acting injectable atypical antipsychotic drug used in the treatment of schizophrenia in adult patients. It is a prodrug of , which acts as a partial agonist at the D2 and 5-HT1A receptors, and as an antagonist at the 5-HT2A receptors . Affecting about 1% of the adult population in the United States and approximately 26 million people worldwide, schizophrenia is a chronic neurological disorder that may result in impairments in cognition and executive functions . The quality of life in patients is greatly reduced due to negative health outcomes, and oftentimes the patients are faced with social stigma and discriminations. Schizophrenia is characterized by positive symptoms such as delusions, hallucinations, thought disorders, and catanoia, and negative symptoms that include social withdrawal, anhedonia, and flattening of emotional responses . D2 receptors have been the most common target for antipsychotic agents used in the treatment of schizophrenia: the positive symptoms are thought to arise from overactivity in the mesolimbic dopaminergic pathway activating D2 receptors, whereas negative symptoms may result from a decreased activity in the mesocortical dopaminergic pathway with D1 receptors predominating . In a randomized, double-blind clinical trial, treatment of aripiprazole lauroxil in adult patients with schizophrenia resulted in improvement of positive and negative symptoms scores at day 85 of treatment . Aripiprazole lauroxil was initially approved by the FDA in October 2015 under the market name Aristada for the treatment of schizophrenia. It is administered via intramuscular injection, and requires the establishment of tolerability prior to dosing in treatment-naïve patients . On July 2nd, a different formulation of aripiprazole lauroxil marketed as Aristada Initio was FDA-approved for immediate initiation of Aristada at any dose. The patients may receive Aristada Initio in combination with a single 30 mg oral dose of aripiprazole to achieve appropriate levels of aripiprazole more rapidly. Long-acting injectable aripiprazole lauroxil displayed comparable efficacy and safety to aripiprazole , and reduced dosing frequency improves patient adherence.

Indications:

This drug is primarily indicated for: Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic disorders. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Aripiprazole lauroxil undergoes metabolic processing primarily in: Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma . Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Aripiprazole lauroxil are crucial for its therapeutic efficacy: Following a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection . The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Aripiprazole lauroxil is an important consideration for its dosing schedule: The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Aripiprazole lauroxil exhibits a strong affinity for binding with plasma proteins: Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Aripiprazole lauroxil from the body primarily occurs through: Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Aripiprazole lauroxil is distributed throughout the body with a volume of distribution of: Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption . Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Aripiprazole lauroxil is a critical factor in determining its safe and effective dosage: In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Aripiprazole lauroxil exerts its therapeutic effects through: Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin levels . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Aripiprazole lauroxil functions by: The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor . The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects . In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment . Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia . 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals . The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects . Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia . 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex . It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner . Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension . Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Aripiprazole lauroxil belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group, classified under the direct parent group Phenylpiperazines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Diazinanes class, specifically within the Piperazines subclass.

Categories:

Aripiprazole lauroxil is categorized under the following therapeutic classes: Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-Antagonists, Adrenergic Antagonists, Agents that produce hypertension, Antidepressive Agents, Antipsychotic Agents, Antipsychotic Agents (Second Generation [Atypical]), Aripiprazole and prodrugs, Central Nervous System Agents, Central Nervous System Depressants, Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 CYP3A7 Substrates, Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, Histamine Antagonists, Histamine H1 Antagonists, Neurotoxic agents, Piperazines, Potential QTc-Prolonging Agents, Psychotropic Drugs, QTc Prolonging Agents, Quinolines, Quinolones, Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome, Serotonin 5-HT2 Receptor Antagonists, Serotonin 5-HT2A Receptor Antagonists, Serotonin Agents, Serotonin Receptor Antagonists, Tranquilizing 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 Aripiprazole lauroxil include:

• Water Solubility:<0.01 mg/mL
• Melting Point: 81-83
• logP: 5.3