Pure antiestrogens,
or selective estrogen receptor degraders (SERDs),
have proven to be effective in treating breast cancer that has progressed
on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved
pure antiestrogen, fulvestrant, is limited in efficacy by its low
bioavailability. The search for orally bioavailable SERDs has continued
for nearly as long as the clinical history of the injection-only fulvestrant.
Oral SERDs that have been developed and tested in patients ranged
from nonsteroidal ER binders containing an acrylic acid or amino side
chain to bifunctional proteolysis-targeting chimera (PROTAC) pure
ER degraders. Structural evolution in the development of oral SERD
molecules has been closely associated with quantifiable ER-degrading
potency, as seen in the structural comparison analysis of acrylic
acid and basic amino side-chain-bearing SERDs. Failure to improve
on fulvestrant in the clinical trials by numerous acidic SERDs and
early basic SERDs is blamed on tolerability and/or insufficient efficacy,
which will likely be overcome by the new-generation basic SERD molecules
and PROTAC ER degraders with improved oral bioavailability, low toxicity,
and superior efficacy of receptor degradation.
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).
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