Aripiprazole lauroxil

Aripiprazole lauroxil, sold under the brand name Aristada among others, is a long-acting injectable atypical antipsychotic that was developed by Alkermes.^[4][5][6] 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.^[4][5][6] Aripiprazole lauroxil was approved by the US Food and Drug Administration (FDA) in October 2015.^[7][8][9]

Aripiprazole lauroxil

Clinical data
Trade names	Aristada, Aristada Initio
Other names	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
AHFS/Drugs.com	Monograph
MedlinePlus	a615048
License data	US DailyMed: Aripiprazole lauroxil
Pregnancy category	AU: C[1]
Routes of administration	Intramuscular
ATC code	None
Legal status
Legal status	US: ℞-only[2][3]
Identifiers
IUPAC name [7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate
CAS Number	1259305-29-7
PubChem CID	49831411
DrugBank	DB14185
ChemSpider	28651973
UNII	B786J7A343
KEGG	D10364
ChEBI	CHEBI:90930
ChEMBL	ChEMBL2219425
CompTox Dashboard (EPA)	DTXSID60154997
ECHA InfoCard	100.261.570
Chemical and physical data
Formula	C36H51Cl2N3O4
Molar mass	660.72 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCCCCCCCCCCC(=O)OCN1C(=O)CCC2=C1C=C(C=C2)OCCCCN3CCN(CC3)C4=C(C(=CC=C4)Cl)Cl
InChI 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

Medical uses

Aripiprazole lauroxil is indicated for the treatment of schizophrenia in adults.^[2]

Aripiprazole lauroxil is a longer-lasting and injectable version of the schizophrenia pill aripiprazole.^[2] Aripiprazole lauroxil, along with other drugs in its family, are not approved for treatment of the elderly with dementia-related psychosis.^[2][10]

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.^[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.^[2]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.^[12] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[13] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[13] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[13] Symptoms generally resolve after a short period of time.^[13]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.^[14] It may also result in reoccurrence of the condition that is being treated.^[15] Rarely tardive dyskinesia can occur when the medication is stopped.^[13]

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.^[16]

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.^[10][2] 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-HT_1A receptors and antagonist activity at 5-HT_2A receptors. Since it is a newly^[when?] approved drug by the FDA, many validation of mechanisms of action are still being studied.^{[2][needs update]}

Pharmacodynamics

Aripiprazole exhibits high affinity for serotonin 5-HT_1A, 5-HT_2A 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.^[2]

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.^[4]

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.^[2]

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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

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.^[4] 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]