In line with the observations that highly proliferative cells tend to have a high polyamine requirement to support growth, it was found that hair follicle, which is one of the most proliferative organ in the body, expresses a high level of ODC activity [44]. Hair growth in humans is a cyclic process with periods of growth (anagen), transition (catagen), and rest (telogen). Using immunocytochemical analysis, Sundberg reported changes in the ODC expression in relation to the hair-follicle growth cycle [45]. In telogen, the ODC expression was detected only in a small group of outer root sheath cells near the ‘bulge’ region, whereas in anagen ODC expression was found in the whole length of the follicle with particularly high levels in the hyperproliferative matrix region. A similar observation was made by Nancarrow et al. [46], who found high levels of ODC in the anagen growth phase and a very low to nearly undetectable ODC level in the catagen and the resting telogen phases. Hynd and Nancarrow observed that among the three major polyamines, spermidine plays the most critical role in hair growth [47]. Their research further demonstrated an important role of polyamines in hair-fiber formation and keratin – gene expression in hair follicles. In contrast to the high level of ODC in growing follicles, its levels in normal epidermis are very low, unless stimulated by a chemical or mechanical agent. Topical application of a tumor promoter, such as phorbol esters causes a rapid and dramatic increase in the epidermal ODC expression [ 48 , 49 ].
The observations that high polyamine levels are probably required for maintaining hair growth, but not the normal epidermal function and turnover, led to a rational investigation of topical ODC inhibitors for controlling hair growth. Among a number of available ODC inhibitors tested, eflornithine was found to be the most effective in reducing follicular ODC, polyamine levels, and the rate of hair growth [50-52]. Eflornithine was also found to be a highly effective hair-growth inhibitor in an established animal model for the androgen- dependent hair growth [52,53]. One of the key issues for any topically applied agent in terms of both its safety and efficacy is the dermal absorption. Preclinical and clinical pharmacokinetic studies showed that topically applied eflornithine is poorly absorbed through the skin.
Being a highly hydrophilic molecule, eflornithine skin penetration remains limited to less than 1% of the applied dose after single or multiple application [53]. In women, the mean percutaneous absorption after the first (single) dose was found to be 0.34%, which reached 0.82% after multiple doses, representing the likely use conditions [54,55]. The absorbed drug was found to be eliminated, essentially unchanged, via the renal route [53]. Based on eflornithine’s favorable preclinical and clinical toxicology and the data from human pharmacokinetic studies, the Gillette Company (now P&G) initiated the development of this molecule as a topical treatment for controlling facial hair growth. The Phase-I trial was conducted in moderately hirsute women as an open-label study using a 10% eflornithine dose in a hydro-alcoholic vehicle. Results of the study indicated no significant adverse events, dermal or systemic, from the drug treatment. The preliminary efficacy observations showed a significant improvement in condition as determined by the clinician scoring on visibility of facial hair, and also the subject’s own perception of their improved appearance [56]. Based on the favorable safety and efficacy outcome from Phase-I testing, a dose ranging Phase-II study was conducted at 0, 5, 10, and 15%, concentration of eflornithine. monohydrochloride. monohydrate in a cream-based formulation. Gillette patented the eflornithine cream formulation based on its physio-chemical and hair-growth reduction activity that was later trademarked as Vaniqa™ [57]. The objective analyses in the Phase-II trial, included hair-length measurements taken by a video-imaging instrument. The results demonstrated a statistically significant hair growth reduction of 47% in the 15% eflorni – thine group compared to a nonsignificant 8% reduction in the vehicle-control group. The hair length-reduction in the 5 and 10% eflornithine groups was 26 and 28%, respectively, that was found to be not statistically different from the vehicle-control group. The physician global scoring of improvement in the condition and the subjects’ own perceptions of treatment benefits were found to be consistent with the objective hair length measures [53]. The effective 15% eflornithine cream from the Phase-II study was carried forward to the Phase-III trials conducted in partnership with Bristol-Myers Squibb Company.