Peringatan Keamanan

LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents MSDS. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively MSDS. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor FDA Label. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia FDA Label.

Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated FDA Label.

Aripiprazole lauroxil

DB14185

small molecule approved investigational

Deskripsi

Aripiprazole lauroxil is a long-acting injectable atypical antipsychotic drug used in the treatment of schizophrenia in adult patients. It is a prodrug of aripiprazole, which acts as a partial agonist at the D2 and 5-HT1A receptors, and as an antagonist at the 5-HT2A receptors A34289.

Affecting about 1% of the adult population in the United States and approximately 26 million people worldwide, schizophrenia is a chronic neurological disorder that may result in impairments in cognition and executive functions A34289. The quality of life in patients is greatly reduced due to negative health outcomes, and oftentimes the patients are faced with social stigma and discriminations. Schizophrenia is characterized by positive symptoms such as delusions, hallucinations, thought disorders, and catanoia, and negative symptoms that include social withdrawal, anhedonia, and flattening of emotional responses T28. D2 receptors have been the most common target for antipsychotic agents used in the treatment of schizophrenia: the positive symptoms are thought to arise from overactivity in the mesolimbic dopaminergic pathway activating D2 receptors, whereas negative symptoms may result from a decreased activity in the mesocortical dopaminergic pathway with D1 receptors predominating T28. In a randomized, double-blind clinical trial, treatment of aripiprazole lauroxil in adult patients with schizophrenia resulted in improvement of positive and negative symptoms scores at day 85 of treatment A34289, A34301.

Aripiprazole lauroxil was initially approved by the FDA in October 2015 under the market name Aristada for the treatment of schizophrenia. It is administered via intramuscular injection, and requires the establishment of tolerability prior to dosing in treatment-naïve patients FDA Label. On July 2nd, a different formulation of aripiprazole lauroxil marketed as Aristada Initio was FDA-approved for immediate initiation of Aristada at any dose. The patients may receive Aristada Initio in combination with a single 30 mg oral dose of aripiprazole to achieve appropriate levels of aripiprazole more rapidly. Long-acting injectable aripiprazole lauroxil displayed comparable efficacy and safety to aripiprazole A34301, and reduced dosing frequency improves patient adherence.

Struktur Molekul 2D

Berat 660.72
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg [FDA Label].
Volume Distribusi Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption [FDA Label]. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier [FDA Label].
Klirens (Clearance) In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg [A34375].

Absorpsi

Following a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection FDA Label. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections FDA Label.

Metabolisme

Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma FDA Label. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly A34289.

Rute Eliminasi

Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces F397.

Interaksi Obat

1792 Data
Oxcarbazepine The metabolism of Aripiprazole lauroxil can be increased when combined with Oxcarbazepine.
Lorlatinib The metabolism of Aripiprazole lauroxil can be increased when combined with Lorlatinib.
Pegvisomant The metabolism of Aripiprazole lauroxil can be increased when combined with Pegvisomant.
Calcitriol The metabolism of Aripiprazole lauroxil can be increased when combined with Calcitriol.
Flunisolide The metabolism of Aripiprazole lauroxil can be increased when combined with Flunisolide.
Troglitazone The metabolism of Aripiprazole lauroxil can be increased when combined with Troglitazone.
Butalbital The metabolism of Aripiprazole lauroxil can be increased when combined with Butalbital.
Flucloxacillin The metabolism of Aripiprazole lauroxil can be increased when combined with Flucloxacillin.
Bexarotene The metabolism of Aripiprazole lauroxil can be increased when combined with Bexarotene.
Acetaminophen The metabolism of Aripiprazole lauroxil can be increased when combined with Acetaminophen.
Aminoglutethimide The metabolism of Aripiprazole lauroxil can be increased when combined with Aminoglutethimide.
Beclomethasone dipropionate The metabolism of Aripiprazole lauroxil can be increased when combined with Beclomethasone dipropionate.
Progesterone The metabolism of Aripiprazole lauroxil can be increased when combined with Progesterone.
Griseofulvin The metabolism of Aripiprazole lauroxil can be increased when combined with Griseofulvin.
Secobarbital The metabolism of Aripiprazole lauroxil can be increased when combined with Secobarbital.
Cerivastatin The metabolism of Aripiprazole lauroxil can be increased when combined with Cerivastatin.
Betamethasone The metabolism of Aripiprazole lauroxil can be increased when combined with Betamethasone.
Lansoprazole The metabolism of Aripiprazole lauroxil can be increased when combined with Lansoprazole.
Quinine The metabolism of Aripiprazole lauroxil can be increased when combined with Quinine.
Dicloxacillin The metabolism of Aripiprazole lauroxil can be increased when combined with Dicloxacillin.
Cyclophosphamide The metabolism of Aripiprazole lauroxil can be increased when combined with Cyclophosphamide.
Rofecoxib The metabolism of Aripiprazole lauroxil can be increased when combined with Rofecoxib.
Bosentan The metabolism of Aripiprazole lauroxil can be increased when combined with Bosentan.
Vinblastine The metabolism of Aripiprazole lauroxil can be increased when combined with Vinblastine.
Fluocinolone acetonide The metabolism of Aripiprazole lauroxil can be increased when combined with Fluocinolone acetonide.
Thiopental The metabolism of Aripiprazole lauroxil can be increased when combined with Thiopental.
Medroxyprogesterone acetate The metabolism of Aripiprazole lauroxil can be increased when combined with Medroxyprogesterone acetate.
Nafcillin The metabolism of Aripiprazole lauroxil can be increased when combined with Nafcillin.
Rifabutin The metabolism of Aripiprazole lauroxil can be increased when combined with Rifabutin.
Triamcinolone The metabolism of Aripiprazole lauroxil can be increased when combined with Triamcinolone.
Testosterone The metabolism of Aripiprazole lauroxil can be increased when combined with Testosterone.
Clofibrate The metabolism of Aripiprazole lauroxil can be increased when combined with Clofibrate.
Tamoxifen The metabolism of Aripiprazole lauroxil can be increased when combined with Tamoxifen.
Hydrocortisone The metabolism of Aripiprazole lauroxil can be increased when combined with Hydrocortisone.
Modafinil The metabolism of Aripiprazole lauroxil can be increased when combined with Modafinil.
Ethotoin The metabolism of Aripiprazole lauroxil can be increased when combined with Ethotoin.
Hydrocortamate The metabolism of Aripiprazole lauroxil can be increased when combined with Hydrocortamate.
Etoposide The metabolism of Aripiprazole lauroxil can be increased when combined with Etoposide.
Phenylbutazone The metabolism of Aripiprazole lauroxil can be increased when combined with Phenylbutazone.
Mifepristone The metabolism of Aripiprazole lauroxil can be increased when combined with Mifepristone.
Methylphenobarbital The metabolism of Aripiprazole lauroxil can be increased when combined with Methylphenobarbital.
Terbinafine The metabolism of Aripiprazole lauroxil can be increased when combined with Terbinafine.
Prednisolone The metabolism of Aripiprazole lauroxil can be increased when combined with Prednisolone.
Felbamate The metabolism of Aripiprazole lauroxil can be increased when combined with Felbamate.
Norgestimate The metabolism of Aripiprazole lauroxil can be increased when combined with Norgestimate.
Methylprednisolone The metabolism of Aripiprazole lauroxil can be increased when combined with Methylprednisolone.
Metyrapone The metabolism of Aripiprazole lauroxil can be increased when combined with Metyrapone.
Probenecid The metabolism of Aripiprazole lauroxil can be increased when combined with Probenecid.
Nifedipine The metabolism of Aripiprazole lauroxil can be increased when combined with Nifedipine.
Sulfinpyrazone The metabolism of Aripiprazole lauroxil can be increased when combined with Sulfinpyrazone.
Ifosfamide The metabolism of Aripiprazole lauroxil can be increased when combined with Ifosfamide.
Rifapentine The serum concentration of aripiprazole, an active metabolite of Rifapentine, can be decreased when used in combination with Aripiprazole lauroxil.
Ketamine The metabolism of Aripiprazole lauroxil can be increased when combined with Ketamine.
Budesonide The metabolism of Aripiprazole lauroxil can be increased when combined with Budesonide.
Paclitaxel The metabolism of Aripiprazole lauroxil can be increased when combined with Paclitaxel.
Corticotropin The metabolism of Aripiprazole lauroxil can be increased when combined with Corticotropin.
Cefradine The metabolism of Aripiprazole lauroxil can be increased when combined with Cefradine.
Amobarbital The metabolism of Aripiprazole lauroxil can be increased when combined with Amobarbital.
Aprobarbital The metabolism of Aripiprazole lauroxil can be increased when combined with Aprobarbital.
Cortisone acetate The metabolism of Aripiprazole lauroxil can be increased when combined with Cortisone acetate.
Barbital The metabolism of Aripiprazole lauroxil can be increased when combined with Barbital.
Deferasirox The metabolism of Aripiprazole lauroxil can be increased when combined with Deferasirox.
Genistein The metabolism of Aripiprazole lauroxil can be increased when combined with Genistein.
Tesmilifene The metabolism of Aripiprazole lauroxil can be increased when combined with Tesmilifene.
Oritavancin The metabolism of Aripiprazole lauroxil can be increased when combined with Oritavancin.
Clevidipine The metabolism of Aripiprazole lauroxil can be increased when combined with Clevidipine.
Tocilizumab The metabolism of Aripiprazole lauroxil can be increased when combined with Tocilizumab.
Armodafinil The metabolism of Aripiprazole lauroxil can be increased when combined with Armodafinil.
Etravirine The metabolism of Aripiprazole lauroxil can be increased when combined with Etravirine.
Avasimibe The metabolism of Aripiprazole lauroxil can be increased when combined with Avasimibe.
Isavuconazonium The metabolism of Aripiprazole lauroxil can be increased when combined with Isavuconazonium.
Artemether The metabolism of Aripiprazole lauroxil can be increased when combined with Artemether.
Fosaprepitant The metabolism of Aripiprazole lauroxil can be increased when combined with Fosaprepitant.
Seratrodast The metabolism of Aripiprazole lauroxil can be increased when combined with Seratrodast.
Formestane The metabolism of Aripiprazole lauroxil can be increased when combined with Formestane.
Glycerol phenylbutyrate The metabolism of Aripiprazole lauroxil can be increased when combined with Glycerol phenylbutyrate.
Dabrafenib The serum concentration of Aripiprazole lauroxil can be decreased when it is combined with Dabrafenib.
Barbexaclone The metabolism of Aripiprazole lauroxil can be increased when combined with Barbexaclone.
Siltuximab The metabolism of Aripiprazole lauroxil can be increased when combined with Siltuximab.
Eslicarbazepine acetate The metabolism of Aripiprazole lauroxil can be increased when combined with Eslicarbazepine acetate.
Dexamethasone isonicotinate The metabolism of Aripiprazole lauroxil can be increased when combined with Dexamethasone isonicotinate.
Asunaprevir The metabolism of Aripiprazole lauroxil can be increased when combined with Asunaprevir.
Isavuconazole The metabolism of Aripiprazole lauroxil can be increased when combined with Isavuconazole.
Sarilumab The metabolism of Aripiprazole lauroxil can be increased when combined with Sarilumab.
Delafloxacin The metabolism of Aripiprazole lauroxil can be increased when combined with Delafloxacin.
Alpelisib The metabolism of Aripiprazole lauroxil can be increased when combined with Alpelisib.
Brigatinib The metabolism of Aripiprazole lauroxil can be increased when combined with Brigatinib.
Enasidenib The metabolism of Aripiprazole lauroxil can be increased when combined with Enasidenib.
Testosterone cypionate The metabolism of Aripiprazole lauroxil can be increased when combined with Testosterone cypionate.
Testosterone enanthate The metabolism of Aripiprazole lauroxil can be increased when combined with Testosterone enanthate.
Estradiol acetate The metabolism of Aripiprazole lauroxil can be increased when combined with Estradiol acetate.
Estradiol benzoate The metabolism of Aripiprazole lauroxil can be increased when combined with Estradiol benzoate.
Estradiol cypionate The metabolism of Aripiprazole lauroxil can be increased when combined with Estradiol cypionate.
Estradiol dienanthate The metabolism of Aripiprazole lauroxil can be increased when combined with Estradiol dienanthate.
Estradiol valerate The metabolism of Aripiprazole lauroxil can be increased when combined with Estradiol valerate.
Hydrocortisone acetate The metabolism of Aripiprazole lauroxil can be increased when combined with Hydrocortisone acetate.
Hydrocortisone succinate The metabolism of Aripiprazole lauroxil can be increased when combined with Hydrocortisone succinate.
Ivosidenib The metabolism of Aripiprazole lauroxil can be increased when combined with Ivosidenib.
Warfarin The metabolism of Aripiprazole lauroxil can be increased when combined with Warfarin.
Vitamin E The metabolism of Aripiprazole lauroxil can be increased when combined with Vitamin E.

Target Protein

D(2) dopamine receptor DRD2
5-hydroxytryptamine receptor 1A HTR1A
5-hydroxytryptamine receptor 2A HTR2A
5-hydroxytryptamine receptor 1B HTR1B
5-hydroxytryptamine receptor 1D HTR1D
5-hydroxytryptamine receptor 1E HTR1E
D(1A) dopamine receptor DRD1
D(1B) dopamine receptor DRD5
D(3) dopamine receptor DRD3
D(4) dopamine receptor DRD4
5-hydroxytryptamine receptor 2C HTR2C
5-hydroxytryptamine receptor 3A HTR3A
5-hydroxytryptamine receptor 6 HTR6
5-hydroxytryptamine receptor 7 HTR7
Histamine H1 receptor HRH1
Alpha-1A adrenergic receptor ADRA1A
Alpha-1B adrenergic receptor ADRA1B
Alpha-2A adrenergic receptor ADRA2A
Alpha-2B adrenergic receptor ADRA2B
Alpha-2C adrenergic receptor ADRA2C
Muscarinic acetylcholine receptor M1 CHRM1
Muscarinic acetylcholine receptor M2 CHRM2
Muscarinic acetylcholine receptor M3 CHRM3
Muscarinic acetylcholine receptor M4 CHRM4
Muscarinic acetylcholine receptor M5 CHRM5

Referensi & Sumber

Artikel (PubMed)
  • PMID: 27630522
    Cruz MP: Aripiprazole Lauroxil (Aristada): An Extended-Release, Long-Acting Injection For the Treatment of Schizophrenia. P T. 2016 Sep;41(9):556-9.
  • PMID: 27668044
    Raedler LA: Aripiprazole Lauroxil (Aristada): Long-Acting Atypical Antipsychotic Injection Approved for the Treatment of Patients with Schizophrenia. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):40-3.
  • PMID: 28342578
    Potkin SG, Risinger R, Du Y, Zummo J, Bose A, Silverman B, Stankovic S, Ehrich E: Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation. Schizophr Res. 2017 Dec;190:115-120. doi: 10.1016/j.schres.2017.03.003. Epub 2017 Mar 23.
  • PMID: 20643630
    Seeman P: Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses. 2010 Apr;4(1):56-73. doi: 10.3371/CSRP.4.1.5.
  • PMID: 25756003
    Rohde M, M Rk N, Hakansson AE, Jensen KG, Pedersen H, Dige T, J Rgensen EB, Holm R: Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug. Results Pharma Sci. 2014 May 2;4:19-25. doi: 10.1016/j.rinphs.2014.04.002. eCollection 2014.
  • PMID: 15015905
    Lieberman JA: Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18(4):251-67.
Textbook
  • ISBN: 978-0-7020-3471-8
    45. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 553-557). Edinburgh: Elsevier/Churchill Livingstone.

Contoh Produk & Brand

Produk: 5 • International brands: 0
Produk
  • Aristada
    Injection, suspension, extended release • 441 mg/1.6mL • Intramuscular • US • Approved
  • Aristada
    Injection, suspension, extended release • 662 mg/2.4mL • Intramuscular • US • Approved
  • Aristada
    Injection, suspension, extended release • 882 mg/3.2mL • Intramuscular • US • Approved
  • Aristada
    Injection, suspension, extended release • 1064 mg/3.9mL • Intramuscular • US • Approved
  • Aristada Initio
    Injection, suspension, extended release • 675 mg/2.4mL • Intramuscular • US • Approved

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