Aripiprazole lauroxil

Aripiprazole lauroxil
Clinical data
Trade namesAristada, 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.comMonograph
MedlinePlusa615048
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 InfoCard100.261.570 Edit this at Wikidata
Chemical and physical data
FormulaC36H51Cl2N3O4
Molar mass660.72 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, is a long-acting injectable atypical antipsychotic that was developed by Alkermes.[3][4][5] 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.[3][4][5] Aripiprazole lauroxil was approved by the U.S. Food and Drug Administration (FDA) on 5 October 2015.[6][7]

Medical uses

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Aripiprazole lauroxil extended release injection gained FDA approval in 2015, as a treatment for adults with schizophrenia. Like any long-term acting injectable, aripiprazole lauroxil provides assurance to families and health care professionals that patients receive therapeutic medication throughout the day.[8]

Aripiprazole lauroxil is injected into the arm or buttocks of a patient by a health care professional once every four to six weeks. Aripiprazole lauroxil is a longer-lasting and injectable version of the schizophrenia pill aripiprazole, which means that the treatment is available in two doses. Aripiprazole lauroxil, along with other drugs in its family, are not approved for treatment of elderly patients with dementia-related psychosis.[8][9]

Schizophrenia

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The approval of aripiprazole lauroxil from the Food and Drug Administration in 2015 was solely for the treatment of schizophrenia in adults. The ability to supplement aripiprazole lauroxil with oral supplements of aripiprazole allows for dosing flexibility, which is important for the treatment of schizophrenia, as symptoms and intensity of the disease vary greatly from patient to patient. Additionally, as in concurrence with its sister drug aripiprazole, aripiprazole lauroxil is similar in effect of typical antipsychotic drugs.[10] In the sister drug aripiprazole, side effects for patients were less frequently extrapyramidal[clarification needed] than most antipsychotic drugs.[citation needed]

Side effects

[edit]
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.[11]

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.[12]

Discontinuation

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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

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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.[8]

Pharmacology

[edit]

Mechanism of action

[edit]

Arristada is injected intramuscularly as an atypical antipsychotic. In one 12-week clinical trial involving 622 participants, the efficacy of extended aripiprazole was demonstrated.[9][12] 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.[12][needs update]

Pharmacodynamics

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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.[12]

Pharmacokinetics

[edit]

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.[3]

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.[12]

Pharmacokinetics of long-acting injectable antipsychotics
Medication Brand name Class Vehicle Dosage Tmax t1/2 single t1/2 multiple logPc Ref
Aripiprazole lauroxil Aristada Atypical Watera 441–1064 mg/4–8 weeks 24–35 days ? 54–57 days 7.9–10.0
Aripiprazole monohydrate Abilify Maintena Atypical Watera 300–400 mg/4 weeks 7 days ? 30–47 days 4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks 3–9 days ? 21–25 days 7.9 [17]
Clopentixol decanoate Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [18]
Flupentixol decanoate Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [18][19]
Fluphenazine decanoate Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks 1–2 days 1–10 days 14–100 days 7.2–9.0 [20][21][22]
Fluphenazine enanthate Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [21]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [23]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [24][25]
Olanzapine pamoate Zyprexa Relprevv Atypical Watera 150–405 mg/2–4 weeks 7 days ? 30 days –
Oxyprothepin decanoate Meclopin Typical ? ? ? ? ? 8.5–8.7
Paliperidone palmitate Invega Sustenna Atypical Watera 39–819 mg/4–12 weeks 13–33 days 25–139 days ? 8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ? 27 days 8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks 2–3 days ? 4–7 days 6.4–7.2 [26]
Pipotiazine palmitate Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [19]
Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ? 8.4
Risperidone Risperdal Consta Atypical Microspheres 12.5–75 mg/2 weeks 21 days ? 3–6 days –
Zuclopentixol acetate Clopixol Acuphase Typical Viscoleob 50–200 mg/1–3 days 1–2 days 1–2 days 4.7–4.9
Zuclopentixol decanoate Clopixol Depot Typical Viscoleob 50–800 mg/2–4 weeks 4–9 days ? 11–21 days 7.5–9.0
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

[edit]

In contrast to many other depot antipsychotics, aripiprazole lauroxil is described as a non-ester chemical modification.[27] It is specifically N-lauroyloxymethylaripiprazole.[27] However, the N-lauroyloxymethyl moiety contains a laurate ester, technically making aripiprazole lauroxil an antipsychotic ester.[28] More specifically, aripiprazole lauroxil is the laurate ester of N-hydroxymethylaripiprazole.[3] 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.[28][27]

References

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  1. ^ a b "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 Oct 2023.
  3. ^ a b c d Rohde M, M Rk N, Håkansson AE, Jensen KG, Pedersen H, Dige T, J Rgensen EB, Holm R (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.
  4. ^ a b 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.
  5. ^ a b Meltzer HY, Risinger R, Nasrallah HA, Du Y, Zummo J, Corey L, Bose A, Stankovic S, Silverman BL, Ehrich EW (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.
  6. ^ 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.
  7. ^ "Aristada (Aripiprazole lauroxil) FDA Approval History".
  8. ^ a b c "Aristada intramuscular : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD". WebMD. Retrieved 2016-04-18.
  9. ^ a b "New Medical Devices". P & T. 40 (11): 716–774. November 2015. PMC 4634342. PMID 26609204.
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  11. ^ "ARISTADA (aripiprazole lauroxil) | Treatment Prescribing Information". aristada.com. Archived from the original on 2016-04-03. Retrieved 2016-04-18.
  12. ^ a b c d e "DailyMed - ARISTADA- aripiprazole lauroxil injection, suspension, extended release". dailymed.nlm.nih.gov. Retrieved 2016-04-18.
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  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. ^ 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.
  18. ^ a b 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.
  19. ^ a b Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  20. ^ 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.
  21. ^ a b 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.
  22. ^ 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.
  23. ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, Marsboom RH, Hérin VV, Schaper WK (November 1970). "The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug". Arzneimittel-Forschung. 20 (11): 1689–98. PMID 4992598.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ a b c Correll CU, Kim E, Sliwa JK, Hamm W, Gopal S, Mathews M, Venkatasubramanian R, Saklad SR (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.
  28. ^ a b 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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