Aripiprazole

From Wikipedia, the free encyclopedia

Jump to: navigation, search
 This article or section is in the middle of an expansion or major revamping. You are welcome to assist in its construction by editing it as well. This template was placed by Aurochs (talk · contribs).
Not to be confused with Dapiprazole.
Aripiprazole
Systematic (IUPAC) name
7-[4-[4-(2,3-dichlorophenyl)
piperazin-1-yl]butoxy]-
3,4-dihydro-1H-quinolin-2-one
Identifiers
CAS number 129722-12-9
ATC code N05AX12
PubChem 60795
DrugBank APRD00638
ChemSpider 54790
Chemical data
Formula C23H27Cl2N3O2 
Mol. mass 448.385
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 87%
Protein binding >99%
Metabolism liver
Half life 75h (active metabolite : 94h)
Excretion feces and urine
Therapeutic considerations
Licence data

EU EMEA:link, US FDA:link
Pregnancy cat.

C (USA)
Legal status

℞ Prescription only
Routes oral (via tablets, orodispersable tablets, and oral solution); intramuscular

Aripiprazole (air-ee-PIP-ruh-zole) (marketed as Abilify; also known as OPC-14597) was approved by the Food and Drug Administration (FDA) on November 15, 2002 for the treatment of schizophrenia, the sixth atypical antipsychotic medication of its kind. More recently it received FDA approval for the treatment of acute manic and mixed episodes associated with bipolar disorder, and as an adjunct for the treatment of depression.[1] Aripiprazole was developed by Otsuka in Japan; in the U.S., Otsuka America markets the drug jointly with Bristol-Myers Squibb.

Contents

[edit] Therapeutic uses

[edit] Bipolar disorder

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10-17 and in adults.[2] Several double-blind, placebo-controlled trials support this use.[3][4][5][6] In addition, it is often used as maintenance therapy, either on its own or in conjunction with a mood stabilizer such as lithium or valproate. This use is also supported by a handful of studies.[7][8] Aripiprazole is at least as effective as haloperidol at reducing manic symptoms,[9] and is much better tolerated by patients.[10]

Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness[11][12] (with one finding a reduction in anhedonia symptoms[13]), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo.[14] One study reported depression as a side effect of the drug.[15]

[edit] Pharmacodynamics

Aripiprazole's mechanism of action is different from the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). Rather than antagonizing the D2 receptor, aripiprazole appears to be a D2 partial agonist[16][17] and selective agonist.[18] Aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor.[19][20] Aripiprazole has moderate affinity for histamine and α-adrenergic receptors and for the serotonin transporter, and no appreciable affinity for cholinergic muscarinic receptors.[21]

D2 and D3 receptor occupancy levels are high, with average levels ranging between ~71% at 2mg/day to ~96% at 40mg/day.[22][23] Most atypical antypsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.[24]

[edit] Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3-5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. Its elimination half-life is about 94 hours. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.[21]

[edit] Patent status and availability

Otsuka's patent on aripiprazole expires on October 20, 2014;[25] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.[2] Barr Laboratories initiated a patent challenge under the Hatch-Waxman Act in March 2007.[26] This challenge is still in court as of 11 December 2008.

Aripiprazole is available in 2mg, 5mg, 10mg, 15mg, 20mg, and 30mg tablets. Aripiprazole is also available as 10mg and 15mg orally-disintegrating tablets, 1mg/1mL solution and 7.5mg/mL intramuscular injection.[27]

[edit] Side effects

Common side effects: Akathisia, headache, unusual tiredness or weakness, nausea, vomiting, an uncomfortable feeling in the stomach, constipation, light-headedness, trouble sleeping, restlessness, sleepiness, shaking, and blurred vision.

Uncommon side effects: Uncontrollable twitching or jerking movements, tremors, seizure, and weight gain. Some people may feel dizzy, especially when getting up from a lying or sitting position, or may experience a fast heart rate.

Rare side effects: Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate (neuroleptic malignant syndrome).

Very rare side effects: Allergic reaction (such as swelling in the mouth or throat, itching, rash), increased production of saliva, speech disorder, nervousness, agitation, fainting, reports of abnormal liver test values, inflammation of the pancreas, muscle pain, weakness, stiffness, or cramps.

As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.

While taking aripiprazole some elderly patients with dementia have suffered from stroke or 'mini' stroke. Other patients may experience high blood sugar or the onset or worsening of diabetes.

[edit] Drug interactions

Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes is known to increase and decrease, respectively, plasma levels of aripiprazole.[28]

Aripiprazole may change the subjective effects of alcohol. One study[29] found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study[30] found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole.

[edit] See also

[edit] References

  1. ^ Hitti, Miranda (20 November 2007). "FDA OKs Abilify for Depression". WebMD. http://www.webmd.com/depression/news/20071120/fda-oks-abilify-for-depression. Retrieved on 8 December 2008. 
  2. ^ a b "Patent and Exclusivity Search Results". Electronic Orange Book. US Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021436&Product_No=001&table1=OB_Rx. Retrieved on 8 December 2008. 
  3. ^ Keck PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G (September 2003). "A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania". Am J Psychiatry 160 (9): 1651–8. doi:10.1176/appi.ajp.160.9.1651. PMID 12944341. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=12944341. 
  4. ^ Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Impellizzeri C, Kaplita S, Rollin L, Iwamoto T (July 2006). "Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study". J. Psychopharmacol. (Oxford) 20 (4): 536–46. doi:10.1177/0269881106059693. PMID 16401666. 
  5. ^ Vieta E, T'joen C, McQuade RD, Carson WH, Marcus RN, Sanchez R, Owen R, Nameche L (October 2008). "Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study". Am J Psychiatry 165 (10): 1316–25. doi:10.1176/appi.ajp.2008.07101560. PMID 18381903. 
  6. ^ Keck PE, Orsulak PJ, Cutler AJ, Sanchez R, Torbeyns A, Marcus RN, McQuade RD, Carson WH (January 2009). "Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study". J Affect Disord 112 (1-3): 36–49. doi:10.1016/j.jad.2008.05.014. PMID 18835043. 
  7. ^ Keck PE, Calabrese JR, McIntyre RS, McQuade RD, Carson WH, Eudicone JM, Carlson BX, Marcus RN, Sanchez R (October 2007). "Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo". J Clin Psychiatry 68 (10): 1480–91. PMID 17960961. 
  8. ^ Keck PE, Calabrese JR, McQuade RD, Carson WH, Carlson BX, Rollin LM, Marcus RN, Sanchez R (April 2006). "A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder". J Clin Psychiatry 67 (4): 626–37. PMID 16669728. 
  9. ^ Young AH, Oren DA, Lowy A, McQuade RD, Marcus RN, Carson WH, Spiller NH, Torbeyns AF, Sanchez R (January 2009). "Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study". Br J Psychiatry 194 (1): 40–8. doi:10.1192/bjp.bp.108.049965. PMID 19118324. 
  10. ^ Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Swanink R, Iwamoto T (September 2005). "Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial". Br J Psychiatry 187: 235–42. doi:10.1192/bjp.187.3.235. PMID 16135860. 
  11. ^ Mazza M, Squillacioti MR, Pecora RD, Janiri L, Bria P (December 2008). "Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial". Expert Opin Pharmacother 9 (18): 3145–9. doi:10.1517/14656560802504490. PMID 19040335. 
  12. ^ Dunn RT, Stan VA, Chriki LS, Filkowski MM, Ghaemi SN (September 2008). "A prospective, open-label study of Aripiprazole mono- and adjunctive treatment in acute bipolar depression". J Affect Disord 110 (1-2): 70–4. doi:10.1016/j.jad.2008.01.004. PMID 18272230. 
  13. ^ Mazza M, Squillacioti MR, Pecora RD, Janiri L, Bria P (January 2009). "Effect of aripiprazole on self-reported anhedonia in bipolar depressed patients". Psychiatry Res 165 (1-2): 193–6. doi:10.1016/j.psychres.2008.05.003. PMID 18973955. 
  14. ^ Thase ME, Jonas A, Khan A, Bowden CL, Wu X, McQuade RD, Carson WH, Marcus RN, Owen R (February 2008). "Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies". J Clin Psychopharmacol 28 (1): 13–20. doi:10.1097/jcp.0b013e3181618eb4. PMID 18204335. 
  15. ^ Muzina DJ, Momah C, Eudicone JM, Pikalov A, McQuade RD, Marcus RN, Sanchez R, Carlson BX (May 2008). "Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study". Int. J. Clin. Pract. 62 (5): 679–87. doi:10.1111/j.1742-1241.2008.01735.x. PMID 18373615. 
  16. ^ Lawler CP et al. (1999). "Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes". Neuropsychopharmacology 20 (6): 612–27. doi:10.1016/S0893-133X(98)00099-2. PMID 10327430. 
  17. ^ Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (December 2005). "Intrinsic Efficacy of Antipsychotics at Human D2, D3, and D4 Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D2/D3 Partial Agonist". J Pharmacol Exp Ther 315 (3): 1278–87. doi:10.1124/jpet.105.092155. PMID 16135699. 
  18. ^ Urban JD et al. (2007). "Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways". Neuropsychopharmacology 32 (1): 67–77. doi:10.1038/sj.npp.1301071. PMID 16554739. 
  19. ^ Stark, AD et al (2007). "Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies". Psychopharmacology (Berl) 190 (3): 373-382. doi:10.1007/s00213-006-0621-y. PMID 17242925. 
  20. ^ Shapiro, DA et al (2003). "Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology". Neuropsychopharmacology 28 (8): 1400-1411. doi:10.1038/sj.npp.1300203. PMID 12784105. 
  21. ^ a b "Abilify (Aripiprazole) - Clinical Pharmacology". DrugLib.com. 14 February 2007. http://www.druglib.com/druginfo/abilify/pharmacology/. Retrieved on 8 December 2008. 
  22. ^ Kegeles, LS et al. (2008). "Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D2 Receptors by Aripiprazole in Schizophrenia with PET and [18F]Fallypride". Neuropsychopharmacology 33 (13): 3111–3125. doi:10.1038/npp.2008.33. PMID 18418366. 
  23. ^ Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF (August 2002). "Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride". Neuropsychopharmacology 27 (2): 248–59. doi:10.1016/S0893-133X(02)00304-4. PMID 12093598. 
  24. ^ "In This Issue". Am J Psychiatry 165 (8): A46. August 2008. doi:10.1176/appi.ajp.2008.165.8.A46. 
  25. ^ Oshiro, Yasuo; Seiji Sato & Nobuyuki Kurahashi, "Carbostyril derivatives", US 5006528, published October 20, 1989, issued April 9, 1991
  26. ^ Barr Pharmaceuticals, Inc. (2007-03-20). Barr Confirms Filing an Application with a Paragraph IV Certification for ABILIFY(R) Tablets. Press release. http://phx.corporate-ir.net/phoenix.zhtml?c=60908&p=irol-newsArticle&ID=975763&highlight=. Retrieved on 2008-12-23. 
  27. ^ "Abilify (Aripiprazole) - Indications and Dosage". DrugLib.com. 14 February 2007. http://www.druglib.com/druginfo/abilify/indications_dosage/. Retrieved on 11 January 2009. 
  28. ^ "Abilify (Aripiprazole) - Warnings and Precautions". DrugLib.com. 14 February 2007. http://www.druglib.com/druginfo/abilify/warnings_precautions/. Retrieved on 8 December 2008. 
  29. ^ Kranzler, Henry R. et al (2008). "Effects of Aripiprazole on Subjective and Physiological Responses to Alcohol". Alcoholism: Clinical and Experimental Research 32 (4): 573–579. doi:10.1111/j.1530-0277.2007.00608.x. PMID 18261195. 
  30. ^ Konstantin Voronin, Patrick Randall, Hugh Myrick, Raymond Anton (2008). "Aripiprazole Effects on Alcohol Consumption and Subjective Reports in a Clinical Laboratory Paradigm—Possible Influence of Self-Control". Alcoholism: Clinical and Experimental Research 32 (11): 1954–1961. doi:10.1111/j.1530-0277.2008.00783.x. PMID 18782344. 

[edit] External links

v • d • e
Psycholeptics: antipsychotics - primarily dopamine antagonists (N05A)
Typical
Other
Atypical
Other D2 selective
D4 selective
Retrieved from "http://en.wikipedia.org/wiki/Aripiprazole"
Personal tools