Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double-Blind, Placebo-Controlled Phase II Trial
Oukseub Lee, Melissa Pilewskie, Scott Karlan, Mary B Tull, Kelly Benante, Yanfei Xu, Luis Blanco, Irene Helenowski, Masha Kocherginsky, Shivangi Yadav, Omid Hosseini, Nora Hansen, Kevin Bethke, Miguel Muzzio, Melissa A Troester, Eileen Dimond, Marjorie Perloff, Brandy Heckman-Stoddard, Seema A Khan, Oukseub Lee, Melissa Pilewskie, Scott Karlan, Mary B Tull, Kelly Benante, Yanfei Xu, Luis Blanco, Irene Helenowski, Masha Kocherginsky, Shivangi Yadav, Omid Hosseini, Nora Hansen, Kevin Bethke, Miguel Muzzio, Melissa A Troester, Eileen Dimond, Marjorie Perloff, Brandy Heckman-Stoddard, Seema A Khan
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.
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Source: PubMed