Aripiprazole lauroxil

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Aripiprazole lauroxil
Aripiprazole lauroxil.svg
Clinical data
Trade names Aristada, Aristada Initio
Other namesN-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
AHFS/Drugs.com Monograph
MedlinePlus a615048
License data
Pregnancy
category
Routes of
administration 		Intramuscular
ATC code
  • None
Legal status
Legal status
Identifiers
  • [7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.261.570 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C36H51Cl2N3O4
Molar mass 660.72 g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCC(=O)OCN1C(=O)CCC2=C1C=C(C=C2)OCCCCN3CCN(CC3)C4=C(C(=CC=C4)Cl)Cl
  • 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
  • Key: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. [5] [6] [7] 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. [5] [6] [7] Aripiprazole lauroxil was approved by the US Food and Drug Administration (FDA) in October 2015. [8] [9] [10]

Contents

Medical uses

Aripiprazole lauroxil is indicated for the treatment of schizophrenia in adults. [3]

Aripiprazole lauroxil is a longer-lasting and injectable version of the schizophrenia pill aripiprazole. [3] Aripiprazole lauroxil, along with other drugs in its family, are not approved for treatment of the elderly with dementia-related psychosis. [3] [11]

Side effects

The most common side effects are akathisia. According to the drug's warning label and safety information, the side effects are large in variety. [12]

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. [3]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. [13] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. [14] Other symptoms may include restlessness, increased sweating, and trouble sleeping. [14] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. [14] Symptoms generally resolve after a short period of time. [14]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. [15] It may also result in reoccurrence of the condition that is being treated. [16] Rarely tardive dyskinesia can occur when the medication is stopped. [14]

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 ]

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. [17]

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. [11] [3] 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? ] approved drug by the FDA, many validation of mechanisms of action are still being studied. [3] [ needs update ]

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. [3]

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 ]

Bioactivation of aripiprazole lauroxil (N-lauroyloxymethylaripiprazole) into aripiprazole, with N-hydroxymethylaripiprazole as an intermediate. Bioactivation of aripiprazole lauroxil into aripiprazole.jpg
Bioactivation of aripiprazole lauroxil (N-lauroyloxymethylaripiprazole) into aripiprazole, with N-hydroxymethylaripiprazole as an intermediate.

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. [3]

Pharmacokinetics of long-acting injectable antipsychotics
MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
Aripiprazole lauroxilAristada Atypical Water a441–1064 mg/4–8 weeks24–35 days ?54–57 days7.9–10.0
Aripiprazole monohydrate Abilify Maintena Atypical Water a300–400 mg/4 weeks7 days ?30–47 days4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks3–9 days ?21–25 days7.9 [18]
Clopentixol decanoate Sordinol Depot Typical Viscoleo b50–600 mg/1–4 weeks4–7 days ?19 days9.0 [19]
Flupentixol decanoate Depixol Typical Viscoleo b10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2 [19] [20]
Fluphenazine decanoate Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0 [21] [22] [23]
Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4 [22]
Fluspirilene Imap, Redeptin Typical Water a2–12 mg/1 week1–8 days7 days ?5.2–5.8 [24]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9 [25] [26]
Olanzapine pamoate Zyprexa Relprevv Atypical Water a150–405 mg/2–4 weeks7 days ?30 days–
Oxyprothepin decanoate Meclopin Typical  ? ? ? ? ?8.5–8.7
Paliperidone palmitate Invega Sustenna Atypical Water a39–819 mg/4–12 weeks13–33 days25–139 days ?8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ?27 days8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks2–3 days ?4–7 days6.4–7.2 [27]
Pipotiazine palmitate Piportil Longum Typical Viscoleo b25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6 [20]
Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ?8.4
Risperidone Risperdal Consta Atypical Microspheres 12.5–75 mg/2 weeks21 days ?3–6 days–
Zuclopentixol acetate Clopixol Acuphase Typical Viscoleo b50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
Zuclopentixol decanoate Clopixol Depot Typical Viscoleo b50–800 mg/2–4 weeks4–9 days ?11–21 days7.5–9.0
Note: All by intramuscular injection. Footnotes:a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources:Main: See template.

Chemistry

In contrast to many other depot antipsychotics, aripiprazole lauroxil is described as a non-ester chemical modification. [28] It is specifically N-lauroyloxymethylaripiprazole. [28] However, the N-lauroyloxymethyl moiety contains a laurate ester, technically making aripiprazole lauroxil an antipsychotic ester. [29] More specifically, aripiprazole lauroxil is the laurate ester of N-hydroxymethylaripiprazole. [5] 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. [29] [28]

References

  1. ↑ "Aripiprazole Use During Pregnancy". Drugs.com. 5 February 2020. Retrieved 29 August 2020.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. 1 2 3 4 5 6 7 8 9 "Aristada- aripiprazole lauroxil injection, suspension, extended release". DailyMed. 28 January 2025. Retrieved 16 February 2025.
  4. ↑ "Aristada Initio- aripiprazole lauroxil injection, suspension, extended release". DailyMed. 28 January 2025. Retrieved 16 February 2025.
  5. 1 2 3 4 Rohde M, M Rk N, Håkansson AE, Jensen KG, Pedersen H, Dige T, et al. (2014). "Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug". Results Pharma Sci. 4: 19–25. doi:10.1016/j.rinphs.2014.04.002. PMC   4050360 . PMID   25756003.
  6. 1 2 Turncliff R, Hard M, Du Y, Risinger R, Ehrich EW (2014). "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". Schizophr. Res. 159 (2–3): 404–10. doi:10.1016/j.schres.2014.09.021. PMID   25266547. S2CID   1036686.
  7. 1 2 Meltzer HY, Risinger R, Nasrallah HA, Du Y, Zummo J, Corey L, et al. (2015). "A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia". J Clin Psychiatry. 76 (8): 1085–90. doi: 10.4088/JCP.14m09741 . PMID   26114240.
  8. ↑ Citrome L (2015). "Aripiprazole Long-Acting Injectable Formulations for Schizophrenia: Aripiprazole Monohydrate and Aripiprazole Lauroxil". Expert Rev Clin Pharmacol. 9 (2): 169–86. doi:10.1586/17512433.2016.1121809. PMID   26573020. S2CID   207208248.
  9. ↑ "Aristada (Aripiprazole lauroxil) FDA Approval History".
  10. ↑ "Aristada (aripiprazole lauroxil)". U.S. Food and Drug Administration (FDA). 5 October 2015. Retrieved 16 February 2025.
  11. 1 2 "New Medical Devices". P & T. 40 (11): 716–774. November 2015. PMC   4634342 . PMID   26609204.
  12. ↑ "ARISTADA (aripiprazole lauroxil) | Treatment Prescribing Information". aristada.com. Archived from the original on 3 April 2016. Retrieved 18 April 2016.
  13. ↑ Joint Formulary Committee B, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN   978-0-85369-845-6. 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.
  14. 1 2 3 4 5 Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN   9780198527480.
  15. ↑ Moncrieff J (July 2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID   16774655. S2CID   6267180.
  16. ↑ Sacchetti E, Vita A, Siracusano A, Fleischhacker W (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN   9788847026797.
  17. ↑ "Aristada intramuscular : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD". WebMD. Retrieved 18 April 2016.
  18. ↑ Parent M, Toussaint C, Gilson H (1983). "Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation". Current Therapeutic Research. 34 (1): 1–6.
  19. 1 2 Jørgensen A, Overø KF (1980). "Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels". Acta Psychiatrica Scandinavica. Supplementum. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID   6931472.
  20. 1 2 Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  21. ↑ Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). "Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches". The Journal of Clinical Psychiatry. 45 (5 Pt 2): 50–9. PMID   6143748.
  22. 1 2 Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". British Journal of Clinical Pharmacology. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC   1429660 . PMID   444352.
  23. ↑ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
  24. ↑ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, et al. (November 1970). "The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug". Arzneimittel-Forschung. 20 (11): 1689–98. PMID   4992598.
  25. ↑ Beresford R, Ward A (January 1987). "Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis". Drugs. 33 (1): 31–49. doi:10.2165/00003495-198733010-00002. PMID   3545764.
  26. ↑ Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). "Pharmacokinetics of haloperidol decanoate. A 2-year follow-up". International Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID   7185768.
  27. ↑ Larsson M, Axelsson R, Forsman A (1984). "On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate". Current Therapeutic Research. 36 (6): 1071–88.
  28. 1 2 3 Correll CU, Kim E, Sliwa JK, Hamm W, Gopal S, Mathews M, et al. (January 2021). "Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview". CNS Drugs. 35 (1): 39–59. doi:10.1007/s40263-020-00779-5. PMC   7873121 . PMID   33507525.
  29. 1 2 Ma Z, Zhang H, Wang Y, Tang X (April 2019). "Development and evaluation of intramuscularly administered nano/microcrystal suspension". Expert Opin Drug Deliv. 16 (4): 347–361. doi:10.1080/17425247.2019.1588248. PMID   30827123. S2CID   73504046.
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