TEMPORAL HAIR GROWTH CHARACTERISTICS AND BIODISPOSITION OF BIMATOPROST IN SKIN

David F Woodward1, Jenny W Wang1, Elaine S-H Tang1, Mayssa Attar2. 1Allergan Inc, Dept of Biological Sciences, USA, 2Allergan Inc, Dept of Pharmacokinetics and Biodisposition, USA

Prostaglandin F2 α ethanolamide ( prostamide F2 α ) is a COX-2 derived product of the endocannabinoid anandamide and has been shown to produce pain and ocular hypotension . Its congener bimatoprost is used as glaucoma therapy and to treat eyelash hypotrichosis and pharmacocosmetically for enhancing eyelash appearance. It is currently under clinical investigation for treating male pattern baldness. Bimatoprost biodisposition in the skin has not been investigated to date, although its metabolic fate has been extensively characterized in the eye . Hair growth was studied on pelage skin in C57/Bl6 mice. Daily topical application of graded doses of bimatoprost to the backs of shaved mice significantly reduced the time of onset for hair growth. Moreover, the time to achieve complete hair regrowth was greatly reduced. No sign of discomfort of any kind was observed for mice that received bimatoprost . Analysis of 0.03% bimatoprost biodisposition in the skin after one and twenty one days of treatment in mice revealed concentrations of 1.33 and 3.61 μg/g tissue, respectively . Bimatoprost was detected only as the intact molecule, no conversion to 17-phenyl PGF2 α was apparent. Bimatoprost (intact) was detected in the blood: 1 day treatment = 1.83 ng/ml, 21 day treatment = 1.56 ng/ml. These data demonstrate that the effect of bimatoprost on hair growth involves only the intact molecule, likely interacting with prostamidereceptors . Bimatoprost biodisposition was also investigated in pig and human skin. In a 14 day study in mini-pig skin, 0.03% bimatoprost resulted in a skin level of 12.5μg/g tissue. This was much higher than observed in mouse skin. In mini-pig skin a small amount of 17-phenyl PGF2 α was detected (30.8 ng/g tissue). Extended treatment protocols with higher doses produced similar results. Hair growth was not studied in mini-pigs. Studies in isolated human skin specimens, using the Franz chamber, revealed that the highest proportion of bimatoprost in the tissue to be associated with the epidermis. Less than 0.06% of the total bimatoprost was recovered as 17-phenyl-PGF2 α.