First-in-human study evaluating safety and pharmacokinetics of endoxifen, a potent estrogen-receptor antagonist for breast cancer.

Abstract

3087 Background: Endoxifen is an active metabolite of tamoxifen, a widely used breast cancer drug. Treatment of breast cancer directly with endoxifen may eliminate tamoxifen metabolism associated variability and avoid a potential serious drug-drug interaction. In this study, the safety, tolerability, and pharmacokinetics (PK) of endoxifen at escalating single doses were assessed in healthy, adult, male and female human subjects. Methods: An open label, single oral dose, randomized, dose escalating parallel study was conducted in 40 healthy male and female fasting subjects. Eight subjects received a single dose of 0.5, 1, 2, or 4 mg endoxifen tablets. Tamoxifen (Nolvadex) 20 mg tablets were administered to eight subjects as reference. Blood samples were collected at predose and up to 528 hours postdose for PK. Results: Single oral dose of endoxifen at 0.5, 1, 2, or 4 mg was safe and well tolerated. Adverse events were not found and no clinically significant changes in laboratory or other safety variables were noted. Endoxifen displays near dose-proportional pharmacokinetics, and small deviations from dose. The drug at all doses was rapidly absorbed with Tmax 6±2.9 h and half-life (t3/4) of 54.9±8.6. Increase in Cmax and AUC appeared proportional to dose when consecutive dose increments were compared. Endoxifen administered at 0.5, 1, 2, or 4 mg resulted in 1.36, 3.8, 5.5, and 14.5 ng/mL Cmax and 99.1, 231, 330, 763 ng.h/mL AUC0-inf, respectively. When compared with endoxifen levels in 20 mg tamoxifen administered subjects, 0.5, 1, 2, and 4 mg endoxifen showed 228%, 804%, and 1,216%, 3,385% higher Cmax, respectively, while Tmax was significantly lower in endoxifen treated subjects. Conclusions: This is the first ever report on human trial demonstrating escalating single oral dose of endoxifen. The results indicated that oral administration of endoxifen is safe and systemically bioavailable in healthy adult human subjects and exhibited linear pharmacokinetics over the dose range of 0.5-4 mg. The drug continues in clinical development as a potentially new therapeutic agent in patients with breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Intas Pharmaceuticals, Jina Pharmaceuticals, Lambda Therapeutic Research Ltd