Adapalene

Adapalene
Clinical data
Trade namesDifferin, others
AHFS/Drugs.comMonograph
MedlinePlusa604001
License data
Pregnancy
category
  • AU: D
Routes of
administration		Topical
Drug classRetinoids
ATC code
Physiological data
ReceptorsRetinoic acid receptor (RAR)
MetabolismKnown to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as parent drug
Legal status
Legal status
Pharmacokinetic data
BioavailabilityVery low[medical citation needed]
MetabolismKnown to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as parent drug
MetabolitesGlucuronides
Elimination half-lifebetween 7 and 51 hours
ExcretionBile duct
Identifiers
  • 6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.149.379 Edit this at Wikidata
Chemical and physical data
FormulaC28H28O3
Molar mass412.529 g·mol−1
3D model (JSmol)
Melting point300 °C (572 °F)
Boiling point606.3 °C (1,123.3 °F)
  • COC1=C(C=C(C=C1)C2=CC3=C(C=C2)C=C(C=C3)C(=O)O)C45CC6CC(C4)CC(C6)C5
  • InChI=InChI=1S/C28H28O3/c1-31-26-7-6-23(21-2-3-22-12-24(27(29)30)5-4-20(22)11-21)13-25(26)28-14-17-8-18(15-28)10-19(9-17)16-28/h2-7,11-13,17-19H,8-10,14-16H2,1H3,(H,29,30) checkY
  • Key:LZCDAPDĜCYOEH-UHFFFAOYSA-N checkY
  (verify)
Adapalene Gel, sold in trade name Differin in China

Adapalene, sold under the brand name Differin among others, 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.[6] Studies have found adapalene is as effective as other retinoids, while causing less irritation.[7] 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.[7] It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide.[7] 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.[8] The Swiss company Galderma developed adapalene.

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.[9][10] An adapalene/benzoyl peroxide combination medication is also available. 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 postinflammatory hyperpigmentation caused by acne.[9] In the long term, it can be used as maintenance therapy.[9]

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. Other non-FDA approved indications that have been reported in the literature include treatment of warts, molluscum contagiosum, Darier's disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.[7]

Side effects

Of the three topical retinoids, adapalene is often regarded as the best tolerated. It can cause mild adverse effects such as photosensitivity, irritation, redness, dryness, itching, and burning, [7] and 1% to 10% of users[11] experience a brief sensation of warmth or stinging, as well as dry skin, peeling and redness during the first two to four weeks using the medication.[9][12] These effects are considered mild and usually decrease over time.[9][12] Serious allergic reactions are rare.[12]

Pregnancy & lactation

Use of topical adapalene in pregnancy has not been well studied but has a theoretical risk of retinoid embryopathy.[13] Thus far, there is no evidence that the cream causes problems in the baby if used during pregnancy.[14]

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.[15]

Interactions

Adapalene has been shown to enhance the efficacy of topical clindamycin, although adverse effects are also increased.[16][17] 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.[18]

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.[19] Furthermore, photodegradation of the molecule is less of a concern in comparison to tretinoin and tazarotene.[7]

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.[3] Controlled trials of chronic users of adapalene have found drug levels in the patients' plasma to be 0.25 ng/mL.[13]

Pharmacodynamics

Adapalene is highly lipophilic. When applied topically, it readily penetrates hair follicles and absorption occurs five minutes after topical application.[7] After penetration into the follicle, adapalene binds to nuclear retinoic acid receptors (namely retinoic acid receptor beta and gamma).[10][13] 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.[7][13] This results in normalization of keratinocyte differentiation, allowing for decreased microcomedone formation, decreased clogging of pores, and increased exfoliation by increasing cell turnover.[7][13][20] Adapalene is also regarded as an anti-inflammatory agent, as it suppresses the inflammatory response stimulated by the presence of Cutibacterium acnes,[7] and inhibits both lipoxygenase activity and the oxidative metabolism of arachidonic acid into prostaglandins.[13]

Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma when applied to epithelial cells such as those found in the skin.[21] 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.[22]

Retinization is a common temporary phenomenon reported by patients when initiating use of retinoids.[23] 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.[23]

Metabolism

Extensive information regarding adapalene metabolism in humans is unavailable, although it is known to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as parent drug[24]

History

Adapalene was a research product of the Swiss company Galderma.[25] Adapalene was approved in 1996 by the US Food and Drug Administration (FDA) for use in the treatment of acne.[26]

Research

A study has concluded that adapalene can be used to treat plantar warts and may help clear lesions faster than cryotherapy.[27] A computational study claims that adapalene can be used as a potential entry inhibitor for Omicron variant of SARS-CoV-2.[28]

References

  1. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 15 August 2023.
  2. ^ "Differin- adapalene gel". DailyMed. 7 December 2022. Retrieved 15 May 2024.
  3. ^ a b "Differin- adapalene cream". DailyMed. 31 October 2022. Retrieved 15 May 2024.
  4. ^ "Differin- adapalene gel". DailyMed. 27 December 2023. Retrieved 15 May 2024.
  5. ^ "Differin- adapalene lotion". DailyMed. 19 April 2023. Retrieved 15 May 2024.
  6. ^ Rolewski SL (October 2003). "Clinical review: topical retinoids". Dermatology Nursing. 15 (5): 447–50, 459–65. PMID 14619325.
  7. ^ a b c d e f g h i j Tolaymat L, Dearborn H, Zito PM (June 2023). "Adapalene". StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. PMID 29494115.
  8. ^ Asai Y, Baibergenova A, Dutil M, Humphrey S, Hull P, Lynde C, et al. (February 2016). "Management of acne: Canadian clinical practice guideline". CMAJ. 188 (2): 118–126. doi:10.1503/cmaj.140665. PMC 4732962. PMID 26573753.
  9. ^ a b c d e Kolli SS, Pecone D, Pona A, Cline A, Feldman SR (June 2019). "Topical Retinoids in Acne Vulgaris: A Systematic Review". American Journal of Clinical Dermatology. 20 (3): 345–365. doi:10.1007/s40257-019-00423-z. PMID 30674002. S2CID 59225325.
  10. ^ a b Thiboutot DM, Dréno B, Abanmi A, Alexis AF, Araviiskaia E, Barona Cabal MI, et al. (February 2018). "Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne" (PDF). Journal of the American Academy of Dermatology. 78 (2 Suppl 1): S1–S23.e1. doi:10.1016/j.jaad.2017.09.078. hdl:10067/1492720151162165141. PMID 29127053. S2CID 31654121.
  11. ^ "Differin". Swedish Drug Formulary. Retrieved 11 December 2017.
  12. ^ a b c "Adapalene Gel". WebMD. Retrieved 11 December 2017.
  13. ^ a b c d e f Piskin S, Uzunali E (August 2007). "A review of the use of adapalene for the treatment of acne vulgaris". Therapeutics and Clinical Risk Management. 3 (4): 621–624. PMC 2374937. PMID 18472984.
  14. ^ "FDA approves Differin Gel 0.1% for over-the-counter use to treat acne". Food and Drug Administration (Press release). 8 July 2016. Retrieved 14 July 2016.
  15. ^ "Adapalene", Drugs and Lactation Database (LactMed), National Library of Medicine (US), 2006, PMID 30000483, retrieved 13 March 2019
  16. ^ Wolf JE, Kaplan D, Kraus SJ, Loven KH, Rist T, Swinyer LJ, et al. (September 2003). "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. doi:10.1067/S0190-9622(03)01152-6. PMID 12963897.
  17. ^ Jain GK, Ahmed FJ (2007). "Adapalene pretreatment increases follicular penetration of clindamycin: in vitro and in vivo studies". Indian Journal of Dermatology, Venereology and Leprology. 73 (5): 326–329. doi:10.4103/0378-6323.34010. PMID 17921613.
  18. ^ Jain GK, Ahmed FJ (2007). "Adapalene pretreatment increases follicular penetration of clindamycin: in vitro and in vivo studies". Indian Journal of Dermatology, Venereology and Leprology. 73 (5): 326–329. doi:10.4103/0378-6323.34010. PMID 17921613.
  19. ^ Martin B, Meunier C, Montels D, Watts O (October 1998). "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. doi:10.1046/j.1365-2133.1998.1390s2008.x. PMID 9990414. S2CID 43287596.
  20. ^ "DIFFERIN® (adapalene) Gel, 0.3%" (PDF). Retrieved 12 March 2019.
  21. ^ Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G (2006). "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging. 1 (4): 327–348. doi:10.2147/ciia.2006.1.4.327. PMC 2699641. PMID 18046911.
  22. ^ Michel S, Jomard A, Démarchez M (October 1998). "Pharmacology of adapalene". The British Journal of Dermatology. 139 (Suppl 52): 3–7. doi:10.1046/j.1365-2133.1998.1390s2003.x. PMID 9990413. S2CID 23084886.
  23. ^ a b "Differin Gel: An Over-the-Counter Retinoid for Acne". www.differin.com. Retrieved 25 March 2019.
  24. ^ https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022502s000PharmR.pdf
  25. ^ US Patent 4717720A, Shroot B, Eustache J, Bernardon J-M, "Benzonaphthalene derivatives and compositions", published 5 January 1988, issued 5 January 1988, assigned to Galderma Research and Development SNC 
  26. ^ "FDA approval of Differin (adapalene) Solution, 0.1%". FDA. 31 May 1996. Retrieved 29 May 2017.
  27. ^ Gupta R, Gupta S (2015). "Topical adapalene in the treatment of plantar warts; randomized comparative open trial in comparison with cryo-therapy". Indian Journal of Dermatology. 60 (1): 102. doi:10.4103/0019-5154.147835. PMC 4318023. PMID 25657417.
  28. ^ Fidan O, Mujwar S, Kciuk M (February 2023). "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. doi:10.1007/s11030-022-10440-6. PMC 9066996. PMID 35507211.