Melanotan I

Mecanismo de acción

Melanotan I is an agonist of the melanocortin-1 receptor (MC1R) on cutaneous melanocytes. Receptor activation stimulates the cAMP/PKA cascade and the transcription factor MITF, upregulating tyrosinase and increasing synthesis of the dark, photoprotective pigment eumelanin; the pharmacology of the melanocortin receptors and their synthetic analogs is summarized in review articles (Hadley and Dorr, 2006). This MC1R effect is not confined to overall skin tone: according to the US prescribing information, the licensed implant may lead to generalized increased skin pigmentation and to darkening of pre-existing nevi and ephelides. Compared with native α-MSH, the two substitutions norleucine at position 4 and D-phenylalanine at position 7 increase receptor potency and stability against enzymatic degradation (Hadley and Dorr, 2006); in the first clinical description, subcutaneous administration produced measurable skin darkening without UV irradiation as the triggering stimulus, with all participants using a high-potency sunscreen during the trial (Levine et al., 1991). Unlike the cyclic Melanotan II, which non-selectively also activates central MC3R and MC4R signalling, Melanotan I remains structurally close to linear α-MSH (Hadley and Dorr, 2006; Langan et al., 2010); in the pharmacokinetic study in three volunteers, occasional gastrointestinal upset and facial flushing were described as side effects (Ugwu et al., 1997). Pharmacokinetically, subcutaneous injection showed complete bioavailability, no plasma levels were detectable after oral administration, and the beta-phase half-life was 0.8 to 1.7 hours (Ugwu et al., 1997). The licensed dosage form is not an injectable preparation but a subcutaneous implant containing 16 mg of afamelanotide, administered every 60 days in the pivotal trials.

Estado de la evidencia

The early human data come from the University of Arizona: a randomized, placebo-controlled, double-blind trial in 28 healthy white men showed significant skin darkening after ten subcutaneous injections over twelve days, in both poorly tanning (skin type I/II) and well tanning skin types (III/IV), peaking one to three weeks after the end of treatment, with no darkening under placebo (Levine et al., 1991). A pharmacokinetic study in three volunteers found complete subcutaneous bioavailability and a beta-phase half-life of 0.8 to 1.7 hours (Ugwu et al., 1997). Under the INN afamelanotide, the substance was subsequently developed clinically as a 16 mg subcutaneous implant: two multicenter, randomized, placebo-controlled phase 3 trials in 74 patients (EU) and 94 patients (US) with erythropoietic protoporphyria showed longer pain-free time in direct sunlight (US: median 69.4 versus 40.8 hours over 6 months; EU: 6.0 versus 0.8 hours over 9 months) and, in the EU trial, fewer phototoxic reactions (Langendonk et al., 2015). Scenesse has held an EU marketing authorization under exceptional circumstances since 22 December 2014, because complete information could not be obtained given the rarity of the disease; FDA approval followed on 8 October 2019 (NDA 210797). Essential for context: both authorizations apply exclusively to the implant in the EPP indication. The prescribing information for the licensed implant additionally warns of serious hypersensitivity reactions including anaphylaxis and, because of generalized increases in pigmentation and darkening of pre-existing nevi, recommends a full-body skin examination twice a year. The substance is not approved for cosmetic tanning in any country, and injectable vials sold as Melanotan I are not covered by these authorizations; the dermatological literature describes needle sharing, unclear product purity and rapidly darkening nevi in users of unregulated Melanotan I/II products, which can complicate the assessment of pigmented lesions and hence melanoma surveillance (Langan et al., 2010). No conclusions on the efficacy or safety of research-grade material can be drawn from the existing evidence.

Almacenamiento y manipulación

Lyophilized peptides are generally stored cool, dry and protected from light; for long-term storage, temperatures around -20 °C are commonly cited in the literature. After reconstitution, peptide solutions are typically kept refrigerated (2-8 °C) and used within a few days, as stability in solution is limited. Repeated freeze-thaw cycles are considered unfavorable. No product-specific stability data exist for research-grade material; the storage requirements of the licensed implant apply exclusively to the pharmaceutical product.

Preguntas sobre el estado de la investigación

What has Melanotan I been investigated for in research?

Melanotan I was first studied as a pigmentation agent: a placebo-controlled trial in healthy men showed skin darkening without UV exposure, and a pharmacokinetic study characterized bioavailability and half-life after subcutaneous administration. Under the INN afamelanotide, the substance was subsequently tested in phase 3 trials as an implant for the prevention of phototoxic reactions in erythropoietic protoporphyria. Current research additionally uses it as a tool to study MC1R-mediated pigmentation and photoprotection.

Is Melanotan I approved as a medicine?

Yes, but only in a narrowly defined form: under the INN afamelanotide, the substance is approved as a 16 mg subcutaneous implant (Scenesse), in the EU since December 2014 under exceptional circumstances and in the US since October 2019 (NDA 210797), in each case for the prevention of phototoxicity in erythropoietic protoporphyria. The authorizations cover exclusively this implant in this indication. Injectable vials offered as Melanotan I for research purposes are not covered by them, and the substance is not approved for cosmetic tanning in any country.

Fuentes

1. Levine et al., JAMA 1991DOI: 10.1001/jama.1991.03470190078033PMID: 1658407
2. Langan et al., Br J Dermatol 2010 (unregulierte Melanotan-Produkte)DOI: 10.1111/j.1365-2133.2010.09891.xPMID: 20545686
3. Ugwu et al., Biopharmaceutics & Drug Disposition 1997DOI: 10.1002/(sici)1099-081x(199704)18:3<259::aid-bdd20>3.0.co;2-xPMID: 9113347
4. Langendonk et al., NEJM 2015DOI: 10.1056/NEJMoa1411481PMID: 26132941
5. FDA: Scenesse approval letter, NDA 210797 (2019)
6. EMA: Scenesse (EPAR)