Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double-Blind, Placebo-Controlled Phase II Trial

Abstract

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention.

Trial registration: ClinicalTrials.gov NCT04009044.

Conflict of interest statement

Conflict of Interest statement: The authors declared no competing interests for this work.

© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1.

Processing of mastectomy specimen for drug quantitation and evaluation of tissue composition. A. the distance from nipple to lateral edge and to the medial edge of the breast was measured and the half way point was marked between nipple and each edge of breast. Slice (a) was the central slice, through the nipple. Slice (b) was half way between nipple and lateral edge; e.g. if distance from nipple to lateral edge was 10 cm, slice (b) was taken 5 cm lateral to nipple. Slice (c) was half way from nipple to medial edge of breast. The samples were collected as follow: Lay slice (a) flat and collect sample #1 from the area behind the nipple, about 1 cm deep to the nipple papilla and sample #2 from the deepest location in the center of the breast close to the pectoral fascia, but avoiding the retromammary fat. Lay slice (b) flat, collect sample #3 from the subcutaneous fat, and sample #4 from the center of the slice, equidistant between superficial and deep surfaces. Lay slice (c) flat and collect sample #5 from its center, equidistant between superficial and deep surfaces. If tumor is present, lay the slice with the tumor flat and collect sample #6 from the tumor. Slice number and distance from surface were recorded for each sample. If an axillary lymph node was present and there was no known tumor in the breast (i.e. the mastectomy was for risk reduction), the axillary node was taken as sample #7. This was possible in only 5 subjects. B. Each sample was divided into two pieces: 2/3 for drug quantitation and 1/3 for tissue composition analysis. The smaller sample was inked on the outer surface (black color) and fixed in formalin for 6–24 hours. The inner surface of this sample (without ink, facing drug quantitation sample) was embedded face down in paraffin (blue line with arrow). C. This inner surface was sectioned and stained for H&E. Whole slide images of original H&E slides were taken with 20X magnification in Aperio system (left panel of C, upper row of images) and scored digitally for analysis of tissue composition (left panel of C, lower row of images). Digitized images by tissue composition were color coded: green, yellow, magenta for adipose tissue, epithelium, and stroma, respectively. Digitized score was summarized as tissue composition per sampling location per sample (right panel).

Figure 2.

CONSORT diagram showing participant flow through various stages of enrollment and participation.

Figure 3.

Drug distribution in the breast by study arm. A. TPA (CDB4124) concentrations varied by sampling location, regardless treatment arms: oral arm (O) and transdermal arm (T). 10x drug concentration of transdermal arm was shown in graph. B. Although tissue concentration in the transdermal arm was significantly lower than in the oral arm, concentrations varied similarly by location in both treatment arms: the highest in location 2 and 3; the lowest in location 1 and 6 (tumor). C. There was significant correlation of drug distribution between treatment arms. The solid blue circles along the regression line indicate the median tissue drug concentration at each location, and the red numerals indicate the sampling location. D. The adipose fraction of the breast tissue samples was also similar between arms; the open blue squares indicate the % adipose tissue in each sample, and the red numerals indicate the location. E. Drug concentration of both treatment arms were plotted against adipose% of tissue sample in each arm (blue transdermal, pink oral). The slopes are similar across the study arms.