Abstract
Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested. ZB716 was metabolized primarily by CYP2D6 and CYP3A. In human liver microsomes, ZB716 demonstrated relatively low inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (when testosterone was used as the substrate), and no inhibition of CYP2B6 and 3A4 (when midazolam was used as the substrate). In assays for enzyme activity, ZB716 induced CYP1A2, 2B6, and 3A4 in a concentration-dependent manner. Single-dose and repeated-dose pharmacokinetic studies in rats and dogs showed oral bioavailability, dose-proportional drug exposure, and drug accumulation as measured by maximum concentration and area under the concentration–time curve (AUC).
Highlights
Fulvestrant was approved for second-line endocrine treatment in 2002 [1], and recently as a first-line therapy for advanced or metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer [2,3]
The exposure generally increased with dose in a less than or close to dose-proportional manner on both days 1 and 28
Following oral administration of ZB716 at 25, 100, and 200 mg/kg/day, the exposure generally increased with dose in a less than doseproportional manner on both days 1 and 28, except that the values did not increase with dose from 100 to 200 mg/kg/day in females on day 1, or in males on day 28
Summary
Fulvestrant was approved for second-line endocrine treatment in 2002 [1], and recently as a first-line therapy for advanced or metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer [2,3]. Fulvestrant acts as a full estrogen receptor (ER) antagonist that degrades the receptor protein, conferring clinical efficacy in treating patients with progressive disease while on tamoxifen or aromatase inhibitors. Fulvestrant is not orally bioavailable, and its poor pharmacokinetic properties and insufficient drug exposure are believed to limit clinical response, which could be further improved. Clinical studies indicate that at the maximum injectable limit of 500 mg, the therapeutic effect has not reached its optimal level [5]. This unmet clinical need has driven the continued search for an ER-degrading antiestrogen that could achieve greater drug exposure through high potency and oral bioavailability
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