Abstract P6-21-12: Local transdermal therapy (LTT): Drug permeation and distribution of telapristone acetate (TPA) in a pre-surgical window study of women undergoing mastectomy
Authors: Lee O , Pilewskie M , Xu Y , Benante K , Blanco L , Helenowski I , Tull MB , Muzzio M , Jovanovic B , Karlan S , Hansen N , Bethke K , Kulkarni S , Perloff M , Dimond EP , Heckman-Stoddard BM , Khan SA 
Published: May 2019

Abstract
Background: Low uptake and poor adherence to oral drugs for breast cancer prevention and ductal carcinoma in situ has led to an interest in local routes of delivery with the intent of decreasing systemic exposure and reducing toxicity. LTT has emerged as a possible alternative; previous studies have shown selectively higher concentrations in the breast than in the serum with this delivery route. A question related to LTT is whether or not the drug will permeate and distribute throughout the breast, as is expected with oral delivery.
Methods: We conducted a double-blind study of oral versus LTT delivery of the selective progesterone receptor modulator, telapristone acetate (TPA), in a presurgical window setting, enrolling 82 women planning therapeutic or prophylactic mastectomy. We randomized 67 women 1:1, to oral TPA 12 mg daily, or gel TPA applied to both breasts daily (12 mg/breast), for 4 weeks ±1 week. Mastectomy specimens were sampled at 5 non-tumor locations as well as the tumor and lymph node when available. Samples were split in two: drug concentration (conc.) assay using LC-MS/MS and histological evaluation of tissue composition (fat, fibrous stroma, epithelium). The primary endpoint was mean drug conc. across all breast locations (anticipating that the gel would deliver a mean concentration that was &gt;50% of the mean in the oral group). A secondary endpoint was the drug distribution pattern across the breast, expecting that the distribution would be similar. The tumor sample was saved for biomarker assays related to TPA action; these are ongoing, for a pre-planned pooled analysis of data with NCT01800422 (reported in SABCS abstract 851863).
Results: Of 63 evaluable women (33 oral and 30 gel group), 27 had unilateral and 36 had bilateral mastectomy. The mean drug conc. in the oral group was 166.3 ng/G (SE 11.7), and in the gel group was 10.6 ng/G (SE 10.8), (p&lt;.0001). The conc. was variable across the 7 locations tested in both groups. High concentrations were found in the superficial and deep central locations, retroareolar and lateral locations ranked in the middle, and the medial location was discrepant, being high in the oral and low in the gel group. The variation in drug concentration across all locations was not significantly different between groups (Kolmogorov-Smirnov p=0.99). Among women with bilateral mastectomy, drug concentrations were similar between breasts in both oral and gel groups. In the gel group, despite low TPA concentrations, there was evidence of drug metabolism. The major metabolite, CDB 4453 was detectable in 192/193 samples with detectable parent drug. Analysis of drug concentration adjusted for tissue composition is ongoing.
Conclusions: The gel formulation of TPA did not permeate the skin well. However, the drug delivered to the breast was distributed throughout the breast, similar to the oral delivery route, with the highest concentration in the deep central location. These drug distribution data are novel; drug distribution at multiple locations throughout the breast has not previously been shown. Further work is needed to understand breast distribution with formulations known to have good dermal permeation.
Citation Format: Lee O, Pilewskie M, Xu Y, Benante K, Blanco L, Helenowski I, Tull MB, Muzzio M, Jovanovic B, Karlan S, Hansen N, Bethke K, Kulkarni S, Perloff M, Dimond EP, Heckman-Stoddard BM, Khan SA. Local transdermal therapy (LTT): Drug permeation and distribution of telapristone acetate (TPA) in a pre-surgical window study of women undergoing mastectomy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-12.