Radioactive ADME Demonstrates ARV-110’s High Druggability Despite Low Oral Bioavailability

Proteolysis-targeting chimeras (PROTACs) have emerged
as potentially
effective therapeutic medicines, but their high molecular weight and
poor solubility directly impact their oral bioavailability. This work
synthesized 14C-labeled bavdegalutamide (ARV-110) as a
model compound of PROTACs to evaluate its ADME features. Compared
with targeted antitumor drugs, the use of food increased oral bioavailability
of ARV-110 in rats from 10.75% to 20.97%, which is still undesirable.
However, the therapeutic effect of ARV-110 at a low dose was much
better than that of enzalutamide, demonstrating the specific catalytic
medicinal properties of PROTACs. Moreover, the specific distribution
of ARV-110 in subcutaneous prostate tumors was determined by quantitative
whole-body autoradiography (QWBA). Notably, the specificity and activity
of PROTACs take precedence over their oral absorption, and high oral
bioavailability is not necessary to produce excellent therapeutic
effects. This work presents a roadmap for developing future PROTAC
medications from a radioactive drug metabolism and pharmacokinetics
(DMPK) perspective.