Afamelanotide

Chemical formula: C₇₈H₁₁₁N₂₁O₁₉  Molecular mass: 1,646.845 g/mol  PubChem compound: 16197727

Mechanism of action

Afamelanotide is a synthetic tridecapeptide and a structural analogue of α-melanocyte stimulating hormone (α-MSH). Afamelanotide is a melanocortin receptor agonist and binds predominantly to the melanocortin-1 receptor (MC1R). Its binding lasts longer than that of α-MSH. This results in part from afamelanotide’s resistance to immediate degradation by serum or proteolytic enzymes. It presumably undergoes hydrolysis within a short time; its metabolites' pharmacokinetics and pharmacodynamics are not understood yet.

Afamelanotide is thought to mimic the endogenous compound’s pharmacological activity by activating the synthesis of eumelanin mediated by the MC1R receptor.

Eumelanin contributes to photoprotection through different mechanisms including:

  • strong broadband absorption of UV and visible light, where eumelanin acts as a filter
  • antioxidant activity through scavenging of free radicals; and
  • inactivation of the superoxide anion and increased availability of superoxide dismutase to reduce oxidative stress.

Pharmacodynamic properties

Pharmacodynamic effects

Administration of afamelanotide may, therefore, result in increased production of eumelanin in the skin of the EPP patient independently of exposure to sunlight or artificial UV light. This can be accompanied by a darkening of the skin pigmentation in areas with melanocytes which gradually fades unless a further implant is administered.

Pharmacokinetic properties

Dose-finding studies have not been conducted.

The pharmacokinetics of afamelanotide have not been fully characterised yet, i.e. distribution, metabolism or excretion are not clear. No pharmacokinetic information is available on any of its metabolites (active or inactive).

Half-life is approximately 30 minutes.

Following subcutaneous administration of the implant, most of the active substance is released within the first 48 hours with over 90% released by day 5. Plasma levels of afamelanotide are maintained over a number of days. In most clinical studies afamelanotide plasma levels were below the limit of quantitation by day 10. The implant is absorbed by the body within 50 to 60 days after administration.

Data on possible interactions or effects in special populations, e.g. in patients with hepatic or renal impairment are not available.

Paediatric population

No data are available.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.

In repeated dose toxicity studies, the only finding of relevance was an increase in melanin pigmentation in the dog, which is consistent with the active substance’s pharmacological activity. This effect was observed only at exposure levels approximately 8 times higher than human exposure. Inflammation was observed in the Harderian gland in the rat. This finding is not considered relevant to human safety since the Harderian gland is not present in man.

In a fertility study no effects on the reproductive function of male or female Sprague-Dawley rats were observed after subcutaneous application of afamelanotide. A study in Sprague-Dawley rats showed no adverse effects on embryo-fetal development at exposures approximately 135-fold the human exposure (based on Cmax). A second study on embryo-fetal development in Lister-Hooded rats did not achieve sufficient exposure. Pre- and post-natal development of Sprague-Dawley rats was not affected at exposures of about 135-times the human exposure (based on Cmax).

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