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Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders

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Abstract

Afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its activity and stability were higher than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R), and MC1R signaling increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes and modulates inflammation. The loss-of-function variants of the MC1R present in fair-skinned Caucasians are less effectively activated by the natural hormone. Afamelanotide was the first α-MSH analogue to be applied to human volunteers. Ten daily doses of between 0.08 and 0.21 mg/kg in saline injected subcutaneously resulted in long-lasting skin pigmentation and enabled basic pharmacokinetics. Subcutaneous application had full bioavailability, but neither oral nor transdermal application resulted in measurable plasma concentrations or pigmentation response. Two trials in human volunteers showed that neither MC1R variants nor fair skin reduced the afamelanotide-induced increase in skin pigmentation. A controlled-release formulation optimizes administration in man and is effective at a lower dose than the daily saline injections. Promising therapeutic results were published in polymorphic light eruption, erythropoietic protoporphyria (EPP), solar urticaria, Hailey–Hailey disease and vitiligo. In 2014, afamelanotide was approved by the European Medicines Agency for the prevention of phototoxicity in adult patients with EPP. No late effects were reported in volunteers 25 years after the first exposure or after continuous long-term application of up to 8 years in EPP patients, and an immunogenic potential has been excluded. Generally, adverse effects were benign in all trials.

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Article 04 June 2015

Mauro Picardo, Maria L. Dell'Anna, … Alain Taieb

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Authors and Affiliations

  1. Stadtspital Triemli, Porphyria Outpatient Clinics, Zurich, Switzerland

    Elisabeth I. Minder

  2. Stadtspital Triemli, Institute of Laboratory Medicine, Zurich, Switzerland

    Jasmin Barman-Aksoezen & Xiaoye Schneider-Yin

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  1. Elisabeth I. Minder
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Correspondence to Elisabeth I. Minder.

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Funding

Elisabeth I. Minder, Jasmin Barman-Aksoezen and Xiaoye Schneider-Yin were partly supported by grants from the Foundation for Scientific Research of Triemli Hospital, the Foundation for Scientific Research of the University of Zurich, the Hartmann–Müller Foundation, and the Velux Foundation. The immunogenicity studies were partly supported by a grant from Clinuvel Pharmaceutical, Melbourne, VIC, Australia.

Conflict of interest

Elisabeth Minder was the principal investigator of two trials of afamelanotide by Clinuvel Pharmaceutical, Melbourne, VIC, Australia. Jasmin Barman-Aksoezen and Xiaoye Schneider-Yin declare that they have no conflicts of interest that might be relevant to the contents of this article.

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Minder, E.I., Barman-Aksoezen, J. & Schneider-Yin, X. Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clin Pharmacokinet 56, 815–823 (2017). https://doi.org/10.1007/s40262-016-0501-5

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