Chemistry:Adapalene

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Short description: Third-generation topical retinoid
Adapalene
Adapalene structure.svg
Adapalene-3D-balls.png
Clinical data
Trade namesDifferin, Pimpal, Gallet, Adelene, Adeferin
AHFS/Drugs.comMonograph
MedlinePlusa604001
License data
Pregnancy
category
  • AU: D
Routes of
administration		Topical
Drug classRetinoids
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityVery low
ExcretionBile
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC28H28O3
Molar mass412.529 g·mol−1
3D model (JSmol)
  (verify)

Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions.[1] Studies have found adapalene is as effective as other retinoids, while causing less irritation.[2] It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation.[2] It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide.[2] Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent.[3] The Switzerland company Galderma sells adapalene under the brand-name product Differin.

Medical uses

Per the recommendations of the Global Alliance on Improving Outcomes of Acne, retinoids such as adapalene are considered first-line therapy in acne treatment and are to be used either independently or in conjunction with benzoyl peroxide and/or an antimicrobial agent, like clindamycin, for maximum efficacy.[4][5] Furthermore, adapalene, like other retinoids, increases the efficacy and penetration of other topical acne medications that are used in conjunction with topical retinoids as well as hastens the improvement of the post-inflammatory hyperpigmentation caused by acne.[4] In the long term, it can be used as maintenance therapy.[4]

Off-label uses

Adapalene has the unique ability to inhibit keratinocyte differentiation and decrease keratin deposition. This property makes adapalene an effective treatment for keratosis pilaris and callus. It may be used by men undergoing foreskin restoration to reduce excess keratin that forms a layer on the exterior of the human penis after circumcision. Other non-FDA approved indications that have been reported in the literature include treatment of warts, molluscum contagiosum, Darier disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.[2]

Side effects

Adapalene is known to cause mild adverse effects such as photosensitivity, irritation, redness, dryness, itching, and burning.[2] It is common (between 1% and 10% of users)[6] to experience a brief sensation of warmth or stinging, as well as dry skin, peeling and redness during the first 2–4 weeks of using the medication.[4][7] These effects are considered mild and generally decrease over time.[4][7] Any serious allergic reaction is rare.[7] Furthermore, of the three topical retinoids, adapalene is often regarded as the most tolerable.[2]

Pregnancy & lactation

Use of topical adapalene in pregnancy has not been well studied, but has a theoretical risk of retinoid embryopathy.[8] Thus far, there is no evidence that the cream causes problems in the baby if used during pregnancy. Use is at the consumer's own risk.[9]

Topical adapalene has poor systemic absorption and results in low blood levels (less than 0.025 mcg/L) even after long term use, suggesting that there is low risk of harm for a nursing infant.[10] However, it is recommended that the topical medication should not be applied to the nipple or any other area that may come into direct contact with the infant's skin.[10]

Interactions

Adapalene has been shown to enhance the efficacy of topical clindamycin, although adverse effects are also increased.[11][12] Application of adapalene gel to the skin 3–5 minutes before application of clindamycin enhances penetration of clindamycin into the skin, which may enhance the overall efficacy of the treatment as compared to clindamycin alone.[13]

Pharmacology

Unlike the retinoid tretinoin (Retin-A), adapalene has also been shown to retain its efficacy when applied at the same time as benzoyl peroxide due to its more stable chemical structure.[14] Furthermore, photodegradation of the molecule is less of a concern in comparison to tretinoin and tazarotene.[2]

Pharmacokinetics

Absorption of adapalene through the skin is low. A study with six acne patients treated once daily for five days with two grams of adapalene cream applied to 1,000 cm2 (160 sq in) of skin found no quantifiable amounts, or less than 0.35 ng/mL of the drug, in the patients' blood plasma.[15] Controlled trials of chronic users of adapalene have found drug levels in the patients' plasma to be 0.25 ng/mL.[8]

Pharmacodynamics

Adapalene is highly lipophilic. When applied topically, it readily penetrates hair follicles and absorption occurs five minutes after topical application.[2] After penetration into the follicle, adapalene binds to nuclear retinoic acid receptors (namely retinoic acid receptor beta and gamma).[5][8] These complexes then bind to the retinoid X receptor which induces gene transcription by binding to specific DNA sites, thus modulating downstream keratinocyte proliferation and differentiation.[2][8] This results in normalization of keratinocyte differentiation, allowing for decreased microcomedone formation, decreased clogging of pores, and increased exfoliation by increasing cell turnover.[2][8][16] Adapalene is also regarded as an anti-inflammatory agent, as it suppresses the inflammatory response stimulated by the presence of Cutibacterium acnes,[2] and inhibits both lipoxygenase activity and the oxidative metabolism of arachidonic acid into prostaglandins.[8]

Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma when applied to epithelial cells such as those found in the skin.[17] Its agonism of the gamma subtype is largely responsible for adapalene's observed effects. In fact, when adapalene is applied in conjunction with a retinoic acid receptor gamma antagonist, adapalene loses clinical efficacy.[18]

Retinization is a common temporary phenomenon reported by patients when initiating use of retinoids.[19] Within the initial period of treatment, skin can become red, irritated, dry and may burn or itch from retinoid application; however, this tends to resolve within four weeks with once a day use.[19]

History

Adapalene was a research product of the Switzerland company Galderma's France subsidiary Galderma Laboratories.[20] Adapalene was approved in 1996 by the U.S. Food and Drug Administration (FDA) for use in the treatment of acne.[21]

Research

A study has concluded that adapalene can be used to treat plantar warts and may help clear lesions faster than cryotherapy.[22] Computational study claims that the adapalene can be used as a potential entry inhibitor for Omicron variant of SARS-CoV2.[23]

References

  1. ↑ "Clinical review: topical retinoids". Dermatology Nursing 15 (5): 447–50, 459–65. October 2003. PMID 14619325. http://www.medscape.com/viewarticle/464026. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "Adapalene". StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. June 2023. 
  3. ↑ "Management of acne: Canadian clinical practice guideline". CMAJ 188 (2): 118–126. February 2016. doi:10.1503/cmaj.140665. PMID 26573753. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Topical Retinoids in Acne Vulgaris: A Systematic Review". American Journal of Clinical Dermatology 20 (3): 345–365. June 2019. doi:10.1007/s40257-019-00423-z. PMID 30674002. 
  5. ↑ 5.0 5.1 "Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne". Journal of the American Academy of Dermatology 78 (2 Suppl 1): S1–S23.e1. February 2018. doi:10.1016/j.jaad.2017.09.078. PMID 29127053. 
  6. ↑ "Differin". http://www.fass.se/LIF/product?11-1.ILinkListener-documentTabPanel-tabs-tabs~container-tabs-1-link&userType=0&nplId=19960830000022. 
  7. ↑ 7.0 7.1 7.2 "Adapalene Gel". https://www.webmd.com/drugs/2/drug-6442/adapalene-topical/details. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "A review of the use of adapalene for the treatment of acne vulgaris". Therapeutics and Clinical Risk Management 3 (4): 621–624. August 2007. PMID 18472984. 
  9. ↑ "FDA approves Differin Gel 0.1% for over-the-counter use to treat acne". July 8, 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm510362.htm. 
  10. ↑ 10.0 10.1 "Adapalene", Drugs and Lactation Database (LactMed) (National Library of Medicine (US)), 2006, PMID 30000483, http://www.ncbi.nlm.nih.gov/books/NBK501423/, retrieved 2019-03-13 
  11. ↑ "Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized, investigator-blinded study". Journal of the American Academy of Dermatology 49 (3 Suppl): S211–S217. September 2003. doi:10.1067/S0190-9622(03)01152-6. PMID 12963897. 
  12. ↑ "Adapalene pretreatment increases follicular penetration of clindamycin: in vitro and in vivo studies". Indian Journal of Dermatology, Venereology and Leprology 73 (5): 326–329. 2007. doi:10.4103/0378-6323.34010. PMID 17921613. 
  13. ↑ "Adapalene pretreatment increases follicular penetration of clindamycin: in vitro and in vivo studies". Indian Journal of Dermatology, Venereology and Leprology 73 (5): 326–329. 2007. doi:10.4103/0378-6323.34010. PMID 17921613. 
  14. ↑ "Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation". The British Journal of Dermatology 139 (Suppl 52): 8–11. October 1998. doi:10.1046/j.1365-2133.1998.1390s2008.x. PMID 9990414. 
  15. ↑ "DIFFERIN® (adapalene) Cream, 0.1% Label". FDA. May 25, 2000. http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20748lbl.pdf. 
  16. ↑ "DIFFERIN® (adapalene) Gel, 0.3%". https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021753lbl.pdf. 
  17. ↑ "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging 1 (4): 327–348. 2006. doi:10.2147/ciia.2006.1.4.327. PMID 18046911. 
  18. ↑ "Pharmacology of adapalene". The British Journal of Dermatology 139 (Suppl 52): 3–7. October 1998. doi:10.1046/j.1365-2133.1998.1390s2003.x. PMID 9990413. 
  19. ↑ 19.0 19.1 "Differin Gel: An Over-the-Counter Retinoid for Acne". https://www.differin.com/learn/faqs. 
  20. ↑ Shroot B, Eustache J, Bernardon J-M, "Benzonaphthalene derivatives and compositions", US patent Patent 4717720A, published 1988-01-05, issued 1988-01-05, assigned to Galderma Research and Development SNC
  21. ↑ "FDA approval of DIFFERIN® (adapalene) Solution, 0.1%". FDA. May 31, 1996. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020338. 
  22. ↑ "Topical adapalene in the treatment of plantar warts; randomized comparative open trial in comparison with cryo-therapy". Indian Journal of Dermatology 60 (1): 102. 2015. doi:10.4103/0019-5154.147835. PMID 25657417. 
  23. ↑ "Discovery of adapalene and dihydrotachysterol as antiviral agents for the Omicron variant of SARS-CoV-2 through computational drug repurposing". Molecular Diversity 27 (1): 463–475. February 2023. doi:10.1007/s11030-022-10440-6. PMID 35507211. 

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