5-HT1A Receptor; 5-HT2A Receptor; 5-HT2B Receptor; 5-HT2C Receptor; D2 Receptor; D3 Receptor; D4 Receptor

Aripiprazole lauroxil is a dodecanoate ester obtained by formal condensation of the carboxy group of dodecanoic acid with the hydroxy group of 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]methanol. A prodrug for aripiprazole, it is used for treatment of schizophrenia. It has a role as a H1-receptor antagonist, a second generation antipsychotic, a serotonergic agonist and a prodrug. It is a dodecanoate ester, a quinolone, a dichlorobenzene, a N-arylpiperazine, a N-alkylpiperazine, an aromatic ether and a delta-lactam. [1]

The intermediate N-corresponding aripiprazole is involved in the in vivo biotransformation of aripiprazole lauroxil (in-vehicle product; 1.87 mg/mL). Thus, Aripiprazole lauroxil has a high rate of biotransformation, resulting in the synthesis of the observed N-corresponding methyl aripiprazole, according to peripheral data. When animals are given Aristrozole Lauroyl, the concentrations of Aristrozole are very high [1].

In vitro conversion in buffer[2]
To follow the spontaneous conversion from N-hydroxymethyl aripiprazole/aripiprazole lauroxil to aripiprazole, a stock solution in DMSO-d6 was made so the reaction could be started by adding the stock solution into a phosphate buffer, pH 7.4, which thereby contained 0.5% v/v DMSO-d6. The final concentration of N-hydroxymethyl aripiprazole/aripiprazole lauroxil in the buffer was 9 µM equal to the solubility of aripiprazole in water. The degradation was followed at both 25 °C and 37 °C by continuous measurements.[2]
1H NMR spectra were measured at 600.163 MHz on a Bruker AV-III-600 equipped with a 5 mm TCI CryoProbe. Referencing was done to DMSO-d6 (2.51 ppm). Solvent suppression with excitation sculpting using a square 180 pulse of 4 ms was applied on aqueous solutions. Acquisition time was 1.7 s and repetition delay was 3 s A Lorentzian Line broadening of 1.0 Hz was applied before FT, and the aromatic region was baseline corrected manually using a 4th degree polynomial fit before integration.

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In vitro conversion in plasma[2]
An in vitro experiment was conducted in triplicate by adding 30 µL 1 µM aripiprazole lauroxil dissolved in ethanol to 1.47 mL rat plasma from female Sprague Dawley rats at 37 °C. The spiked plasma was stored at 37 °C and 50 µL aliquots were taken at 0.5 and 1.0 h post-spike. The aliquots were immediately treated with 200 µL cold acetonitrile containing 0.4% citric acid and stored at -80 °C until analysed as described in Section 2.7.

Animal/Disease Models: Female SD (SD (Sprague-Dawley)) rats[1]
Doses: 1.87 mg/ml
Route of Administration: Blood samples were collected at 5, 15, 30 minutes and 1, 2, 4, 6, 8 and 24 hrs (hrs (hours)) after administration.
Experimental Results: Displayed clearance: 0.32 ± 0.11 L/h/kg.

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Formulations for the in vivo study [2]
An emulsion for intravenous administration containing each of the three compounds (i.e., aripiprazole, N-hydroxymethyl-aripiprazole or aripiprazole lauroxil) in equimolar concentrations equivalent to 1 mg aripiprazole was produced. The emulsions consisted of compound, 20% w/w fractionated coconut oil, 1.2% w/w lecithin, 2% w/w glycerol and q.s. water. The amount of each compound added was 1 mg aripiprazole/mL, 1.2 mg N-hydroxymethyl-aripiprazole/mL or 1.87 mg aripiprazole lauroxil/mL, i.e., equimolar. Each of the three compounds was dissolved in the oil together with lecithin and gently heated to 50 °C with continuous stirring. Glycerol was added to the aqueous phase as an isotonic agent and the aqueous phase was heated to 50 °C. The two phases were mixed and homogenised to a pre-emulsion by rapid stirring for 1 min. The pre-emulsion was placed on ice and the droplet size was further reduced by means of a homogeniser equipped with a standard microtip at a power output of 5 (Sonifier Cell Disruptor, Model B15, Branson, Pusan, Korea) for 10 min. The formulation was then filtered through a 0.45 µm sterile filter into a sterilised glass bottle with a rubber membrane and a crimped lid.

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In vivo study[2]
The protocol used for the in vivo study in rats was approved by the institutional animal ethics committee in accordance with Danish law regulating experiments on animals and in compliance with EC directive 2010/63/EU, and the NIH guidelines on animal welfare. Female Sprague Dawley rats, weighing 248–276 g on the day of administration, were used for the pharmacokinetic studies (n = 6 per group). The animals were acclimatised for a minimum of 5 days in groups of 2 on wooden bedding in plastic cages, 595 × 380 × 200 mm3, with a stainless steel lid in humidity- and temperature-controlled ventilation cupboards, relative humidity 40–60%, temperature 20 ± 1 °C, light from 6:00–18:00 h. The animals had free access to a standard rodent diet and water ad libitum during the study.[2]
The animals were randomly assigned to three groups (n = 6 per group) receiving either aripiprazole, N-hydroxymethyl-aripiprazole or aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg. The animals were dosed by injection into the tail vein with a submicron emulsion containing a molar concentration equivalent to 1 mg aripiprazole/mL. Blood samples of 100 µL were obtained from the lateral tail vein by individual vein puncture and collected into potassium–EDTA tubes. Samples was taken at 5, 15, 30 min and 1, 2, 4, 6, 8 and 24 h after administration. Plasma was harvested immediately by 10 min of centrifugation at 4 °C, 2765g and stored at -80 °C until analysed. At the end of the experiment, the animals were sacrificed.

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Absorption, Distribution and Excretion
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.
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.
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.
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.

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Metabolism / Metabolites
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.

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Biological Half-Life
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.

Protein Binding
Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin.

[1]. Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents.CNS Drugs. 2018 Mar;32(3):241-257.

[2]. Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug.Results Pharma Sci. 2014 May 2;4:19-25.

Aripiprazole lauroxil is a dodecanoate ester obtained by formal condensation of the carboxy group of dodecanoic acid with the hydroxy group of 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]methanol. A prodrug for aripiprazole, it is used for treatment of schizophrenia. It has a role as a H1-receptor antagonist, a second generation antipsychotic, a serotonergic agonist and a prodrug. It is a dodecanoate ester, a quinolone, a dichlorobenzene, a N-arylpiperazine, a N-alkylpiperazine, an aromatic ether and a delta-lactam.
Aripiprazole lauroxil is a long-acting injectable atypical antipsychotic drug used in the treatment of schizophrenia in adult patients. It is a prodrug of [aripiprazole], 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.
See also: Aripiprazole (has active moiety).

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Drug Indication
Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic disorders.
FDA Label

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Mechanism of Action
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.

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Schizophrenia is a chronic medical condition with periods of remission and relapses over a patient's lifetime. Antipsychotic medications represent the mainstay of treatment for this disease. Long-acting injectable (LAI) formulations of antipsychotics are an attractive alternative to their oral counterparts, as they enhance patient adherence. A number of second-generation antipsychotics (SGAs) are available in LAI formulations. These include paliperidone, aripiprazole, olanzapine, and risperidone. This article reviews the most recently developed and approved of these formulations-aripiprazole monohydrate, aripiprazole lauroxil, and paliperidone palmitate. While all were initially available as once-monthly formulations, a paliperidone palmitate 3-monthly injection formulation has been approved and is the first LAI agent to extend the dosing administration beyond the typical monthly time period. In addition, aripiprazole lauroxil every 6-week and 8-week administration preparations have been developed. LAI preparations of the SGAs have all demonstrated superiority over placebo and are comparable to their oral counterparts in terms of safety and tolerability, if injection site reactions are not taken into account. First-generation antipsychotic LAI preparations (e.g., haloperidol decanoate) have recently been compared with SGA LAI agents, and both formulations demonstrated comparable efficacy with the expected adverse events seen with each drug. Despite their availability, barriers to the use of LAIs remain. Education of both patients and clinicians on the use of LAI formulations and the continued development of these agents are important steps in ensuring these medications are available to the patients they would be most likely to benefit. [1]

659.326

C, 65.44; H, 7.78; Cl, 10.73; N, 6.36; O, 9.69

1259305-29-7

129722-12-9;851220-85-4 (hydrate);1259305-26-4 (cavoxil);1259305-29-7 (lauroxil);

49831411

White to off-white solid powder

81-83

8.743

0

6

20

45

858

0

CCCCCCCCCCCC(=O)OCN1C2=C(C=CC(=C2)OCCCCN3CCN(CC3)C4=CC=CC(=C4Cl)Cl)CCC1=O

DDINXHAORAAYAD-UHFFFAOYSA-N

InChI=1S/C36H51Cl2N3O4/c1-2-3-4-5-6-7-8-9-10-16-35(43)45-28-41-33-27-30(19-17-29(33)18-20-34(41)42)44-26-12-11-21-39-22-24-40(25-23-39)32-15-13-14-31(37)36(32)38/h13-15,17,19,27H,2-12,16,18,20-26,28H2,1H3

[7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate

Aripiprazole lauroxil; 1259305-29-7; Aristada; RDC-3317; ALKS 9072; Aristada initio; ALKS 9070; RDC 3317;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~8.33 mg/mL (~12.61 mM)

Solubility in Formulation 1: ≥ 0.83 mg/mL (1.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)