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

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.

Increased phototoxic burn tolerance time and quality of life in patients with erythropoietic protoporphyria treated with afamelanotide – a three years observational study

“…Afamelanotide is administered subcutaneously as a 16 mg slow release implant formulation with a therapeutic effect of approximately 60 days [ 21 , 25 ]. Of the 39 EPP patients in this study, six started their treatment during the observation period and 33 were already treated with afamelanotide before 2016, i.e., during the clinical trials, compassionate use programs and a special access scheme for therapy reimbursement in Switzerland.…”

Frontiers in alopecia areata pathobiology research

“…Examples of such additional targets and intervention strategies in future AA management include selective IFN-g blockade 123 in contrast to JAK inhibitors, which also block many other signaling pathways 59 ; restoration of HF IP (eg, by long-acting synthetic analogues of a-MSH) 3,124 ; Kv1.3 channel inhibitors 46 ; substance P receptor antagonists 125 ; VIP receptor agonists 48 ; downregulation or inactivation of MICA 94 ; and/or blocking CXCL10. 126 In addition, improved topical delivery systems of tacrolimus to human skin, which restores human HF IP very effectively ex vivo, 50 should be developed 3 to overcome the insufficient depth of penetration of the currently available ointment formulation.…”

Clinical Guide and Update on Porphyrias

“…The a-melanocyte-stimulating hormone analogue afamelanotide (Scenesse, Clinuvel Pharmaceuticals, Melbourne, VIC, Australia) increases skin pigmentation independent of sunlight via the activation of the melanocortin-1 receptor on melanocytes, improving sunlight protection significantly. [116][117][118][119] In a pilot study, 5 patients with EPP were treated with 2 subcutaneous implants of afamelanotide over 120 days, which increased tolerance to artificial light from a mean of 2.2 minutes to 13.3 minutes. Furthermore, 168 patients with EPP from Europe or the United States who were included in 2 phase 3, multicenter, randomized, double-blind, placebo-controlled trials, received 16 mg of afamelanotide, implanted at intervals of 60 days (for as long as 120 days in the United States and as long as 240 days in Europe).…”