Alitretinoin

Last updated
Alitretinoin
Alitretinoin2DACS.svg
Clinical data
Trade names Panretin (gel), Toctino (oral)
AHFS/Drugs.com Monograph
MedlinePlus a601012
License data
Routes of
administration 		Topical, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding Highly bound, no exact figure available [1]
Metabolism Liver (CYP3A4-mediated oxidation, also isomerised to tretinoin) [1]
Elimination half-life 2–10 hours [1]
Excretion Urine (64%), faeces (30%) [1]
Identifiers
  • (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-
    1-cyclohexenyl)nona-2,4,6,8-tetraenoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.111.081 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H28O2
Molar mass 300.442 g·mol−1
3D model (JSmol)
  • O=C(O)\C=C(\C=C\C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C
  • InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8-,16-14+ Yes check.svgY
  • Key:SHGAZHPCJJPHSC-ZVCIMWCZSA-N Yes check.svgY
   (verify)

Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

Contents

Medical uses

Kaposi's sarcoma

In the United States, topical alitretinoin is indicated for the treatment of skin lesions in AIDS-related Kaposi's sarcoma. Alitretinoin is not indicated when systemic therapy against Kaposi's sarcoma is required. [2] It has received EMA (11 October 2000) and FDA (2 March 1999) approval for this indication. [3] [4]

Chronic hand eczema

Alitretinoin has been granted prescription rights in the UK (08/09/2008) for in chronic hand eczema as used by mouth. [5] In May 2009 the National Institute for Health and Clinical Excellence (NICE) issued preliminary guidance [6] on the use of alitretinoin for the treatment of severe chronic hand eczema in adults. The recommendation stated that only patients with severe chronic hand eczema who are unresponsive to potent topical corticosteroids, oral immunosuppressants or phototherapy should receive the drug. Final NICE guidance was expected in August 2009.[ citation needed ]

Interactions with other medications

Alitretinoin must not be used concurrently with other topical medicine. Insect repellents containing DEET should not be used simultaneously with alitretinoin. Drugs that induce cytochrome P450 isoenzymes may reduce alitretinoin plasma levels. [7]

Adverse effects

Systemic use

[1] [4]

Very common (> 10% frequency):

Common (1–10% frequency):

Uncommon (0.1–1% frequency):

Rare (< 0.1% frequency):

Unknown frequency:

  • Anaphylactic reactions
  • Hypersensitivity
  • Depression
  • Mood changes
  • Suicidal ideation
  • Decreased night vision

Topical use

[8]

Very common (>10% frequency):

Common (1-10% frequency):

Contraindications

Pregnancy is an absolute contraindication as with most other vitamin A products, it should also be avoided when it comes to systemic use in any women that is of childbearing potential and not taking precautions to prevent pregnancy. [1] Toctino (the oral capsule formulation of alitretinoin) contains soya oil and sorbitol. Patients who are allergic to peanut, soya or with rare hereditary fructose intolerance should not take this medicine. [1] It is also contraindicated in nursing mothers. [1] The oral formulation of alitretinoin is contraindicated in patients with: [1]

Interactions

It is a CYP3A4 substrate and hence any inhibitor or inducer of this enzyme may alter plasma levels of alitretinoin. [1] It should not be given to patients with excess vitamin A in their system as there is a potential for its actions on the retinoid X receptor to be exacerbated. [1] It may also interact with tetracyclines to cause benign intracranial hypertension. [1]

Overdose

Alitretinoin is a form of vitamin A. Alitretinoin has been administered in oncological clinical studies at dosages of more than 10-times of the therapeutic dosage given for chronic hand eczema. The adverse effects observed were consistent with retinoid toxicity, and included severe headache, diarrhoea, facial flushing and hypertriglyceridemia. These effects were reversible. [1]

Pharmacological properties

Mechanism of action

Alitretinoin is believed to be the endogenous ligand (a substance that naturally occurs in the body that activates this receptor) for retinoid X receptor, but it also activates the retinoic acid receptor. [1] [9] [10] More specifically, alitretinoin is believed to act on intracellular nuclear receptors of the RAR and RXR subtypes. The activated receptors function as transcription factors, which subsequently influence cell proliferation and cell differentiation. [7] [11] [12]

Alitretinoin acts on both keratinocytes and dendritic cells. In keratinocytes, it reduces cytokine expression, while in dendritic cells it inhibits the upregulation of the maturation marker CD83 and the co-stimulatory molecules CD80 and CD86. Consequently, these dendritic cells exhibit diminished T cell activation capacity. [13]

Absorption and distribution in the body

Following oral administration, alitretinoin exhibits variable absorption, which is increased when taken with food. It is extensively bound to plasma proteins. Metabolism occurs in the liver via CYP3A4, forming 4-oxoalitretinoin. The half-life ranges from 2 to 10 hours, and elimination occurs primarily renally.

No significant systemic distribution is observed after dermal application. [12]

Synthesis

Alitretinoin can be synthesized from all-trans retinoic acid through a reaction catalyzed by palladium: [14]

Alitretinoin synthesis.svg

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Toctino 10mg and 30mg soft capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Stiefel. 30 August 2013. Retrieved 1 February 2014.
  2. ↑ "Panretin (Alitretinoin) Drug Information". RxList. November 21, 2000. Archived from the original on 18 December 2008. Retrieved 2009-01-14.
  3. ↑ "Panretin : EPAR - Product Information" (PDF). European Medicines Agency. Eisai Ltd. 14 September 2012.
  4. 1 2 "PANRETIN (alitretinoin) gel [Eisai Inc.]". DailyMed. Eisai Inc. March 2012. Retrieved 1 February 2014.
  5. ↑ Ruzicka T, Larsen FG, Galewicz D, Horváth A, Coenraads PJ, Thestrup-Pedersen K, Ortonne JP, Zouboulis CC, Harsch M, Brown TC, Zultak M (December 2004). "Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial". Archives of Dermatology. 140 (12): 1453–1459. doi: 10.1001/archderm.140.12.1453 . PMID   15611422.
  6. ↑ "NICE guidance documentation". Archived from the original on 2012-05-28. Retrieved 2009-05-07.
  7. 1 2 "Arzneistoffe: Alitretinoin|Panretin®". Pharmazeutische Zeitung . 2016-02-25. Retrieved 2017-06-26.
  8. ↑ "Panretin, (alitretinoin topical), dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 1 February 2014.
  9. ↑ Rowe A (February 1997). "Retinoid X receptors". The International Journal of Biochemistry & Cell Biology. 29 (2): 275–8. doi:10.1016/S1357-2725(96)00101-X. PMID   9147128.
  10. ↑ Dawson MI, Xia Z (January 2012). "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1821 (1): 21–56. doi:10.1016/j.bbalip.2011.09.014. PMC   4097889 . PMID   22020178.
  11. ↑ Björn Lemmer, Kay Brune, ed. (2010), Pharmakotherapie, klinische Pharmakologie (14., überarb. und aktualisierte ed.), Heidelberg: Springer, p. 425, ISBN   978-3-642-10540-1
  12. 1 2 Aditya Kumar Bubna (2015), "Alitretinoin in Dermatology—An Update", Indian Journal of Dermatology , vol. 60, no. 5, p. 520, doi: 10.4103/0019-5154.164426 , PMC   4601442 , PMID   26538721
  13. ↑ Andreas Kislat, Stephan Meller, Rodrigo Mota, Peter A. Gerber, Bettina A. Buhren, Erich Bünemann, Ulrike Wiesner, Thomas Ruzicka, Bernhard Homey (2011), "Alitretinoin – molecular and cellular mechanisms of action", Journal of Translational Medicine , vol. 9, no. Suppl 2, pp. P16, doi: 10.1186/1479-5876-9-S2-P16 , PMC   3242242 {{citation}}: CS1 maint: multiple names: authors list (link)
  14. ↑ CN 103058850,Deng Qingjun, Wang Shaohui,"Method for preparing alitretinoin",published 2013-04-24
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