Topical tamoxifen gel (afimoxifene) is associated with low plasma levels of 4-OHT while achieving therapeutic local antiestrogenic effect in premenopausal women with cyclical mastalgia.
Authors: Goyal A , Mansel R , Le Nestour E , Masini-Etévé V 
Published: December 2010

Abstract
Abstract #2154
Background:4-hydroxytamoxifen(4-OHT) is a potent anti-estrogenic metabolite of tamoxifen with a much higher affinity for estrogen receptors than tamoxifen.We compared the plasma levels of 4-OHT in subjects applying Afimoxifene gel with subjects on oral tamoxifen.We conducted a randomized clinical trial to evaluate the safety and efficacy of topical Afimoxifene gel for the treatment of moderate-to-severe cyclical mastalgia.&#x2028; Methods:Plasma levels of 4-OHT in 19 healthy premenopausal women taking 20 mg/d oral tamoxifen for at least 2 months were compared with those of 16 healthy premenopausal women assigned to apply 4mg 4-OHT in a 0.228% Afimoxifene gel daily for 21 days in a pharmacokinetic(PK) study.Plasma for PK sampling was obtained at multiple time-points.PK parameters of plasma 4-OHT Cmax, and AUC0-24ht were determined.&#x2028; To evaluate the clinical effectiveness of the gel, premenopausal women aged at least 18 years experiencing moderate-to-severe mastalgia were randomized to receive placebo, 2mg or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles.The primary efficacy parameter was change in mean pain intensity, as measured by the Visual Analog Scale(VAS) for the seven worst pain score days within a cycle, from baseline to the fourth cycle.Plasma levels of 4-OHT were assessed once after the second and the fourth menstrual cycles.&#x2028; All plasma levels of 4-OHT were measured in the same central lab, with a GC-MS method with a lower limit of quantification of 5 pg/mL.&#x2028; Results:In the PK studies, the 4-OHT plasma levels following oral tamoxifen administration were 16-18 times higher than 4-OHT levels following 4mg 4-OHT administration by topical gel. At steady state, mean Cmax levels in the Afimoxifene group and oral tamoxifen group were 149+99 pg/mL and 2398+901 pg/mL respectively. The Cave concentrations, derived from AUC0-24h/24, were 117+77 pg/mL(Afimoxifene) and 2078+811 pg/mL(oral tamoxifen).&#x2028; After 4 cycles of gel treatment, statistically significant improvements relative to placebo were measured in mean VAS score in the 4-mg Afimoxifene group(-12.71 mm[95% confidence interval, -0.96 to -24.47; P = 0.034]).Patient global assessment of pain, physician assessment of pain, tenderness on palpation and nodularity following 4 cycles of treatment were significantly improved in the 4-mg group, compared with placebo(P = 0.010 [pain]; P = 0.012 [tenderness]; P = 0.017 [nodularity]).Systemic exposure was low, with mean 4-OHT plasma levels of 50±64 pg/mL. There were no changes in menstrual pattern or plasma hormone levels and no breakthrough vaginal bleeding in patients treated with Afimoxifene.&#x2028; Conclusion:Topical application avoids high systemic exposure to 4-OHT compared with oral tamoxifen, a 16-18-fold difference, thus potentially reducing the risk of systemic side-effects.Afimoxifene is an effective treatment for moderate-to-severe mastalgia in premenopausal women and has the potential to be used for breast cancer chemoprevention/gynecomastia in the future.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2154.