Transpapillary Delivery of Endoxifen for the Prevention and Treatment of Breast Cancer

Tamoxifen is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as afimoxifene (4-hydroxytamoxifen; 4-OHT) and endoxifen (N-desmethyl-4-hydroxytamoxifen) which have 30 to 100 times greater affinity for the Estrogen Receptor (ER) than tamoxifen itself.


Endoxifen (EDX) is the key active metabolite of tamoxifen (TAM) with higher affinity and specificity for estrogen receptors than the parent compound. Endoxifen also inhibits aromatase activity. Tamoxifen is mainly an inactive pro-drug, requiring metabolism into its most important metabolite, endoxifen, for clinical activity. Since the cytochrome P450 – CYP2D6 enzyme is primarily involved in this metabolism, genetic polymorphisms of this enzyme, can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy oftamoxifen treatment. Additionally, drug-induced CYP2D6 inhibition can have the same negative effect on tamoxifen therapy.


Our patented transpapillary system makes it  possible deliver therapeutic concentrations of highly lipophilic drugs, such as Z-endoxifen directly to the breast. The multiple duct openings on the surface of the nipple directly extend into the terminal duct lobular units of the breast. Furthermore, the nipple-areola complex has a thinner epidermis compared to the skin. The nipple-areola complex also has abundant appendages including apocrine, sebaceous and eccrine sweat glands, all of which can serve as potential transport pathways to the underlying breast tissue.


The majority of breast cancers originate from the epithelial cells lining the milk ducts. Although, most breast cancers are localized to the breast, some can progress to invasive, metastatic breast cancer. Ductal carcinoma in-situ (DCIS) is a common breast cancer in women, where localized therapy can be most beneficial. Further, local therapy can replace adjuvant therapy when the cancer is localized to the breast. Transpapillary delivery to the breast would also offer a viable alternative for the 40% of high-risk women who discontinue the use of tamoxifen for breast cancer prevention due to adverse effects.


Transpapillary administration results in high concentrations of highly lipophilic anti-cancer drugs such as Z-endoxifen in the breast and avoids the systemic circulation. When transdermal breast administration is employed lipophilic drugs such as Z-endoxifen must first pass into the systemic circulation before they preferentially partition to the breast and other tissue resulting in both high tissue and serum levels and often leads to adverse systemic effects.


Our transpapillary product by contrast, presents high concentrations of the lipophilic drug e.g. Z-endoxifen, directly to the breast, from there, only a tiny fraction of the drug partitions out into the hydrophilic serum. The low concentration in the serum is the result of the tendency of lipophilic drugs to minimally partition into hydrophilic serum from tissue thus avoiding adverse systemic effects.


Not only can our transpapillary Z-endoxifen produce therapeutic concentrations in the breast using once daily- dosing but those concentrations can be maintained by once or at most twice a week administration. Additionally, therapeutic concentrations can be maintained in the breast with barely detectable levels in the systemic circulation.