Aripiprazole lauroxil, sold under the brand name Aristada, is a long-acting

injectable An injection (often and usually referred to as a "shot" in US English, a "jab" in UK English, or a "jag" in Scottish English and Scots) is the act of administering a liquid, especially a drug, into a person's body using a needle (usually a hypo ...

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...

that was developed by Alkermes. It is an N-acyloxymethyl

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

aripiprazole Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...

that is administered via

intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...

once every four to eight weeks for the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

. Aripiprazole lauroxil was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) on 5 October 2015.

Medical uses

Aripiprazole lauroxil extended release injection gained FDA approval in 2015, as a treatment for adults with

. Like any long-term acting injectable, aripiprazole lauroxil provides assurance to families and health care professionals that patients receive therapeutic medication throughout the day. 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

, 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 Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

-related psychosis.

Schizophrenia

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. In the sister drug aripiprazole, side effects for patients were less frequently extrapyramidal than most antipsychotic drugs.

Side effects

The most common side effects are

akathisia Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back a ...

. According to the drug's warning label and safety information, the side effects are large in variety. The complete list of side effects include: akathisia, Contraindication Cerebrovascular Adverse Reactions (Including Stroke),

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fa ...

, Tardive Dyskinesia, metabolic changes,

Hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

Diabetes Mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

Dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

, weight gain,

Orthostatic Hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

Leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of ...

Neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

Agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...

, seizures, potential for Cognitive and Motor Impairment, difficulties with body temperature regulation,

Dysphagia Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or liq ...

, Injection-Site Reactions (

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

, swelling, redness, irritation at the point of injection),

Dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often int ...

and pregnancy and nursing complications.

Discontinuation

The

British National Formulary The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medici ...

recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. 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. It may also result in reoccurrence of the condition that is being treated. 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. Common adverse reactions, reported in at least 5% of overdose cases, included

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

, and tremor. Other clinically important signs and symptoms of overdoses include

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describe ...

aggression Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...

, atrial fibrillation,

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, ...

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...

, confusion,

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

, depressed level of consciousness,

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...

hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

, loss of consciousness, pneumonia aspiration,

respiratory arrest Respiratory arrest is a sickness caused by apnea (cessation of breathing) or respiratory dysfunction severe enough it will not sustain the body (such as agonal breathing). Prolonged apnea refers to a patient who has stopped breathing for a long pe ...

status epilepticus Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...

, and

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

Pharmacology

Mechanism of action

Arristada is injected intramuscularly as an atypical

antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...

. 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 Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

to N-hydroxymethyl aripirazole. The hydroxymethyl aripirazole is then

hydrolysed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

to aripiprazole. Efficacy could be mediated through a combination of partial agonist activity D2 and

5-HT1A The serotonin 1A receptor (or 5-HT1A receptor) is a subtype of serotonin receptor, or 5-HT receptor, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-c ...

receptors and antagonist activity at

5-HT2A The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is sh ...

receptors. Since it is a newly approved drug by the FDA, many validation of mechanisms of action are still being studied.

Pharmacodynamics

Aripiprazole exhibits high affinity for

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

receptors, dopamine D2, and dopamine D3. Moderate affinity is exhibited for serotonin

5-HT7 The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular ...

, alpha1-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-aripirazole 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. Bioactivation of aripiprazole lauroxil into aripiprazole

Bioactivation of aripiprazole lauroxil into aripiprazole

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.

Chemistry

In contrast to many other depot antipsychotics, aripiprazole lauroxil is described as a non-

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

chemical modification Chemical modification refers to a number of various processes involving the alteration of the chemical constitution or structure of molecules. In chemistry Chemical modification describes the conversion of macromolecules through a chemical react ...

. It is specifically ''N''-lauroyloxymethylaripiprazole. However, the ''N''-lauroyloxymethyl

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

contains a laurate ester, technically making aripiprazole lauroxil an antipsychotic ester. 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

of aripiprazole with ''N''-hydroxymethylaripiprazole as an intermediate.

References

External links

* {{Portal bar , Medicine 7-(4-(4-Phenylpiperazin-1-yl)butoxy)-1H-quinolin-2-ones 2,3-Dichlorophenylpiperazines Antipsychotic esters Laurate esters Prodrugs