aripiprazole lauroxil
{{Short description|Chemical compound}}
{{Use dmy dates|date=February 2025}}
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{{Infobox drug
| image = Aripiprazole lauroxil.svg
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| tradename = Aristada, Aristada Initio
| Drugs.com = {{Drugs.com|monograph|aripiprazole}}
| MedlinePlus = a615048
| DailyMedID = Aripiprazole lauroxil
| pregnancy_AU = C
| pregnancy_AU_comment = {{cite web | title=Aripiprazole Use During Pregnancy | website=Drugs.com | date=5 February 2020 | url=https://www.drugs.com/pregnancy/aripiprazole.html | access-date=29 August 2020}}
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| routes_of_administration = Intramuscular
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| ATC_prefix = None
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| legal_US = Rx-only
| legal_US_comment = {{cite web | title=Aristada- aripiprazole lauroxil injection, suspension, extended release | website=DailyMed | date=28 January 2025 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=17a8d11b-73b0-4833-a0b4-cf1ef85edefb | access-date=16 February 2025}}{{cite web | title=Aristada Initio- aripiprazole lauroxil injection, suspension, extended release | website=DailyMed | date=28 January 2025 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b18fdfd9-31cd-4a2f-9f1c-ebc70d7a9403 | access-date=16 February 2025}}
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| CAS_number = 1259305-29-7
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| PubChem = 49831411
| IUPHAR_ligand =
| DrugBank = DB14185
| ChemSpiderID = 28651973
| UNII = B786J7A343
| KEGG = D10364
| ChEBI = 90930
| ChEMBL = 2219425
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = N-Lauroyloxymethylaripiprazole; ALKS-9070; ALKS-9072; RDC-3317; Dodecanoic acid-[7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2-oxo-1(2H)-quinolinyl]methyl ester
| IUPAC_name = [7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate
| C=36 | H=51 | Cl=2 | N=3 | O=4
| smiles = CCCCCCCCCCCC(=O)OCN1C(=O)CCC2=C1C=C(C=C2)OCCCCN3CCN(CC3)C4=C(C(=CC=C4)Cl)Cl
| StdInChI = 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
| StdInChIKey = DDINXHAORAAYAD-UHFFFAOYSA-N
}}
Aripiprazole lauroxil, sold under the brand name Aristada among others, is a long-acting injectable atypical antipsychotic that was developed by Alkermes.{{cite journal | vauthors = Rohde M, M Rk N, Håkansson AE, Jensen KG, Pedersen H, Dige T, J Rgensen EB, Holm R | title = Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug | journal = Results Pharma Sci | volume = 4 | pages = 19–25 | year = 2014 | pmid = 25756003 | pmc = 4050360 | doi = 10.1016/j.rinphs.2014.04.002 }}{{cite journal | vauthors = Turncliff R, Hard M, Du Y, Risinger R, Ehrich EW | title = Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia | journal = Schizophr. Res. | volume = 159 | issue = 2–3 | pages = 404–10 | year = 2014 | pmid = 25266547 | doi = 10.1016/j.schres.2014.09.021 | s2cid = 1036686 }}{{cite journal | vauthors = Meltzer HY, Risinger R, Nasrallah HA, Du Y, Zummo J, Corey L, Bose A, Stankovic S, Silverman BL, Ehrich EW | title = A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia | journal = J Clin Psychiatry | volume = 76 | issue = 8 | pages = 1085–90 | year = 2015 | pmid = 26114240 | doi = 10.4088/JCP.14m09741 | doi-access = free }} It is an N-acyloxymethyl prodrug of aripiprazole that is administered via intramuscular injection once every four to eight weeks for the treatment of schizophrenia. Aripiprazole lauroxil was approved by the US Food and Drug Administration (FDA) in October 2015.{{cite journal | vauthors = Citrome L | title = Aripiprazole Long-Acting Injectable Formulations for Schizophrenia: Aripiprazole Monohydrate and Aripiprazole Lauroxil | journal = Expert Rev Clin Pharmacol | volume = 9| issue = 2| pages = 169–86| year = 2015 | pmid = 26573020 | doi = 10.1586/17512433.2016.1121809 | s2cid = 207208248 }}{{Cite web|url=https://www.drugs.com/history/aristada.html|title=Aristada (Aripiprazole lauroxil) FDA Approval History}}{{cite web | title=Aristada (aripiprazole lauroxil) | website=U.S. Food and Drug Administration (FDA) | date=5 October 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207533Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20160819020314/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207533Orig1s000TOC.cfm | url-status=dead | archive-date=19 August 2016 | access-date=16 February 2025}}
Medical uses
Aripiprazole lauroxil is indicated for the treatment of schizophrenia in adults.
Aripiprazole lauroxil is a longer-lasting and injectable version of the schizophrenia pill aripiprazole. Aripiprazole lauroxil, along with other drugs in its family, are not approved for treatment of the elderly with dementia-related psychosis.{{cite journal | vauthors = | title = New Medical Devices | journal = P & T | volume = 40 | issue = 11 | pages = 716–774 | date = November 2015 | pmid = 26609204 | pmc = 4634342 }}
Side effects
{{See also|List of adverse effects of aripiprazole}}
The most common side effects are akathisia. According to the drug's warning label and safety information, the side effects are large in variety.{{Cite web|url=http://aristada.com/hcp/schizophrenia-treatment-prescribing|title=ARISTADA (aripiprazole lauroxil) {{!}} Treatment Prescribing Information|website=aristada.com|access-date=18 April 2016|archive-url=https://web.archive.org/web/20160403054222/http://aristada.com/hcp/schizophrenia-treatment-prescribing|archive-date=3 April 2016|url-status=dead}}
The complete list of side effects include: akathisia, contraindication cerebrovascular adverse reactions (including stroke), neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, hyperglycemia/diabetes mellitus, dyslipidemia, weight gain, orthostatic hypotension, leukopenia, neutropenia, agranulocytosis, seizures, potential for cognitive and motor impairment, difficulties with body temperature regulation, dysphagia, injection site reactions (rash, swelling, redness, irritation at the point of injection), dystonia and pregnancy and nursing complications.
=Discontinuation=
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.{{cite book |editor1-first=BMJ | editor = Joint Formulary Committee | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}} Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.{{cite book | vauthors = Haddad P, Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}} Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.{{cite journal | vauthors = Moncrieff J | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x | s2cid = 6267180 }} It may also result in reoccurrence of the condition that is being treated.{{cite book | vauthors = Sacchetti E, Vita A, Siracusano A, Fleischhacker W |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |language=en}} Rarely tardive dyskinesia can occur when the medication is stopped.
= Overdosing =
The largest known case of ingestion with a known outcome involved a 1260 mg of oral aripiprazole, 42 times the recommended dose. The patient survived and fully recovered.{{Citation needed|date=December 2017}}
Common adverse reactions, reported in at least 5% of overdose cases, included vomiting, somnolence, and tremor. Other clinically important signs and symptoms of overdoses include acidosis, aggression, atrial fibrillation, bradycardia, coma, confusion, convulsion, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.{{Cite web|url=http://www.webmd.com/drugs/2/drug-170041/aristada-intramuscular/details|title=Aristada intramuscular : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD|website=WebMD|language=en-US|access-date=18 April 2016}}
Pharmacology
= Mechanism of action =
Arristada is injected intramuscularly as an atypical antipsychotic. In one 12-week clinical trial involving 622 participants, the efficacy of extended aripiprazole was demonstrated. Its mechanism of action is not completely known, but is thought to be converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole. The hydroxymethyl aripiprazole is then hydrolysed to aripiprazole. Efficacy could be mediated through a combination of partial agonist activity D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Since it is a newly{{when|date=August 2020}} approved drug by the FDA, many validation of mechanisms of action are still being studied.{{update inline|date=August 2020}}
= Pharmacodynamics =
Aripiprazole exhibits high affinity for serotonin 5-HT1A, 5-HT2A receptors, dopamine D2, and dopamine D3. Moderate affinity is exhibited for serotonin 5-HT7, α1-adrenergic, dopamine D4, histamine H1, and serotonin re-uptake site. No affinity for cholinergic muscarinic receptors have been found.
= Pharmacokinetics =
Aristada's activity in the body is due to aripiprazole and also dehydro-aripiprazole. Dehydro-aripiprazole has been shown to have affinities for D2 receptors. These D2 receptors have similarities to aripiprazole whereas they represent 30-40% of exposure of aripiprazole in plasma.{{Citation needed|date=December 2017}}
File:Bioactivation of aripiprazole lauroxil into aripiprazole.jpg{{Clear}}
After five to six days of the single intramuscular injection appearance of aripiprazole in circulation, it additionally will be released for 36 days. In the fourth monthly injection, consecutive doses of Aristada will reach steady-state. With additional supplements of the oral aripiprazole at a dosage of 21 days during the first dose of Aristada, aripiprazole concentrations within 4 days can reach therapeutic levels.
{{Pharmacokinetics of long-acting injectable antipsychotics}}
Chemistry
In contrast to many other depot antipsychotics, aripiprazole lauroxil is described as a non-ester chemical modification.{{cite journal | vauthors = Correll CU, Kim E, Sliwa JK, Hamm W, Gopal S, Mathews M, Venkatasubramanian R, Saklad SR | title = Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview | journal = CNS Drugs | volume = 35 | issue = 1 | pages = 39–59 | date = January 2021 | pmid = 33507525 | pmc = 7873121 | doi = 10.1007/s40263-020-00779-5 | url = }} It is specifically N-lauroyloxymethylaripiprazole. However, the N-lauroyloxymethyl moiety contains a laurate ester, technically making aripiprazole lauroxil an antipsychotic ester.{{cite journal | vauthors = Ma Z, Zhang H, Wang Y, Tang X | title = Development and evaluation of intramuscularly administered nano/microcrystal suspension | journal = Expert Opin Drug Deliv | volume = 16 | issue = 4 | pages = 347–361 | date = April 2019 | pmid = 30827123 | doi = 10.1080/17425247.2019.1588248 | s2cid = 73504046 | url = }} More specifically, aripiprazole lauroxil is the laurate ester of N-hydroxymethylaripiprazole. Following cleavage of the laurate ester, N-hydroxymethylaripiprazole is further metabolized to aripiprazole, making aripiprazole lauroxil a prodrug of aripiprazole with N-hydroxymethylaripiprazole as an intermediate.
References
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{{Antipsychotics}}
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