Pimecrolimus

Pimecrolimus is an immunomodulating agent of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis (however, Galderma has been promoting the compound in Canada since early 2007) under the trade name Elidel.

Pimecrolimus
Clinical data
Trade namesElidel
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: B3
Routes of
administration		topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilitylow systemic absorption
Protein binding74%–87%
MetabolismHepatic CYP3A
Identifiers
  • (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-3-{(E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl}-8-ethyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosin-1,7,20,21(4H,23H)-tetrone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.124.895
Chemical and physical data
FormulaC43H68ClNO11
Molar mass810.46 g·mol−1
3D model (JSmol)
  • Cl[C@@H]1CC[C@H](C[C@H]1OC)\C=C(/C)[C@H]2OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@]3(O)O[C@H]([C@H](C[C@@H](C)CC(\C)=C\[C@@H](CC)C(=O)C[C@H](O)[C@H]2C)OC)[C@@H](OC)C[C@H]3C
  • InChI=1S/C43H68ClNO11/c1-10-30-18-24(2)17-25(3)19-36(53-8)39-37(54-9)21-27(5)43(51,56-39)40(48)41(49)45-16-12-11-13-32(45)42(50)55-38(28(6)33(46)23-34(30)47)26(4)20-29-14-15-31(44)35(22-29)52-7/h18,20,25,27-33,35-39,46,51H,10-17,19,21-23H2,1-9H3/b24-18+,26-20+/t25-,27+,28+,29-,30+,31+,32-,33-,35+,36-,37-,38+,39+,43+/m0/s1 checkY
  • Key:KASDHRXLYQOAKZ-ZPSXYTITSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Medical uses

It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis,[1] cutaneous lupus erythematosus,[2] oral lichen planus,[3] vitiligo,[4] and psoriasis.[5][6] Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.[7]

Atopic dermatitis

If topical corticosteroids and moisturisers fail in the treatment of atopic dermatitis, short-term treatment with topical calcineurin inhibitors such as tacrolimus or pimecrolimus may be tried. Both tacrolimus and pimecrolimus are effective and safe to use in AD.[8][9]

Side effects
See also: Immunosuppressants in the treatment of dermatitis

In January 2006, the United States Food and Drug Administration (FDA) announced that Elidel packaging would be required to carry a black box warning regarding the potential increased risk of lymph node or skin cancer, as for the similar drug tacrolimus, whereas current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.[10]

Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the American Academy of Dermatology Association Task Force finds that there is no causal proof that topical immunomodulators cause lymphoma or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism.[11] Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy.[12] A 2023 systematic review and meta-analysis published in The Lancet Child & Adolescent Health further concluded with moderate-certainty evidence that the two drugs were not associated with any increased risk of cancer.[13] However, strong debates and controversies continue regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.[14] Dermatologists' and allergists' professional societies, the American Academy of Dermatology,[15] and the American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states "None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship."[16]

Pharmacology

Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to FKBP1A and also inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.

Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals.[17] Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells.[18] It has lower permeation through the skin than topical steroids or topical tacrolimus[19] although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.[20]

References
  1. Firooz A, Solhpour A, Gorouhi F, Daneshpazhooh M, Balighi K, Farsinejad K, Rashighi-Firoozabadi M, Dowlati Y (2006). "Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial". Archives of Dermatology. 142 (8): 1066–1067. doi:10.1001/archderm.142.8.1066. PMID 16924062.
  2. Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stücker M, Bader A, Altmeyer P, Freitag M (2004). "Pimecrolimus 1% cream for cutaneous lupus erythematosus". J Am Acad Dermatol. 51 (3): 407–410. doi:10.1016/j.jaad.2004.01.044. PMID 15337984.
  3. Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, Nassiri Kashani M, Firooz A (2007). "Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus". J Am Acad Dermatol. 57 (5): 806–813. doi:10.1016/j.jaad.2007.06.022. PMID 17658663.
  4. Boone B, Ongenae K, Van Geel N, Vernijns S, De Keyser S, Naeyaert JM (2007). "Topical pimecrolimus in the treatment of vitiligo". Eur J Dermatol. 17 (1): 55–61. doi:10.1684/ejd.2007.0093 (inactive 1 August 2023). PMID 17324829.{{cite journal}}: CS1 maint: DOI inactive as of August 2023 (link)
  5. Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, Gambichler T (2006). "1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study". Arch Dermatol. 142 (9): 1138–1143. doi:10.1001/archderm.142.9.1138. PMID 16983001.
  6. Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M (2008). "Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study". Dermatology. 216 (2): 133–136. doi:10.1159/000111510. PMID 18216475. S2CID 35741213.
  7. Scheinfeld N (2004). "The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review". Dermatol. Online J. 10 (1): 3. doi:10.5070/D35ZK7V6CS. PMID 15347485.
  8. Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM (July 2015). "Topical tacrolimus for atopic dermatitis". The Cochrane Database of Systematic Reviews. 2015 (7): CD009864. doi:10.1002/14651858.CD009864.pub2. PMC 6461158. PMID 26132597.
  9. Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, et al. (January 2023). "Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis". The Lancet. Child & Adolescent Health. 7 (1): 13–25. doi:10.1016/S2352-4642(22)00283-8. PMID 36370744. S2CID 253470127.
  10. N H Cox & Catherine H Smith (December 2002). "Advice to dermatologists re topical tacrolimus". Therapy Guidelines Committee. British Association of Dermatologists. Archived from the original (DOC) on 2006-05-25.
  11. Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ, Frieden IJ, American Academy of Dermatology Association Task Force (2006). "The use of topical calcineurin inhibitors in dermatology: safety concerns Report of the American Academy of Dermatology Association Task Force". J Am Acad Dermatol. 54 (5): 818–823. doi:10.1016/j.jaad.2006.01.054. PMID 16635663.
  12. Spergel JM, Leung DY (2006). "Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence". Curr Allergy Asthma Rep. 6 (4): 270–274. doi:10.1007/s11882-006-0059-7. PMID 16822378. S2CID 40761750.
  13. Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, et al. (January 2023). "Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis". The Lancet. Child & Adolescent Health. 7 (1): 13–25. doi:10.1016/S2352-4642(22)00283-8. PMID 36370744. S2CID 253470127.
  14. Stern RS (2006). "Topical calcineurin inhibitors labeling: putting the "box" in perspective". Archives of Dermatology. 142 (9): 1233–1235. doi:10.1001/archderm.142.9.1233. PMID 16983018.
  15. "Statement Regarding FDA Decision On Two Eczema Medications By American Academy Of Dermatology". Archived from the original on 2008-04-07. Retrieved 2007-09-24.
  16. "AAAAI" (PDF). Archived from the original (PDF) on 2011-07-18. Retrieved 2007-09-24.
  17. Allen BR, Lakhanpaul M, Morris A, Lateo S, Davies T, Scott G, Cardno M, Ebelin ME, Burtin P, Stephenson TJ (2003). "Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients". Arch Dis Child. 88 (11): 969–973. doi:10.1136/adc.88.11.969. PMC 1719352. PMID 14612358.
  18. Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Bürger A, Stütz A (2003). "Pimecrolimus does not affect Langerhans cells in murine epidermis". Br J Dermatol. 149 (4): 853–857. doi:10.1046/j.1365-2133.2003.05559.x. PMID 14616380. S2CID 26517363.
  19. Billich A, Aschauer H, Aszódi A, Stuetz A (2004). "Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus". Int J Pharm. 269 (1): 29–35. doi:10.1016/j.ijpharm.2003.07.013. PMID 14698574.
  20. Murrell DF, Calvieri S, Ortonne JP, Ho VC, Weise-Riccardi S, Barbier N, Paul CF (November 2007). "A randomized controlled trial of pimecrolimus cream 1% in adolescents and adults with head and neck atopic dermatitis and intolerant of, or dependent on, topical corticosteroids". The British Journal of Dermatology. 157 (5): 954–959. doi:10.1111/j.1365-2133.2007.08192.x. PMID 17935515. S2CID 34706897.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.