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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-01, Vol.69 (2_Supplement), p.2154
• Main Authors: Goyal, A, Mansel, R, Le Nestour, E, Masini-Etévé, V
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS-2154

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.
 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.
 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.
 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.
 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).
 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