Effect of carbamazepine on the pharmacokinetics of vepdegestrant, a PROteolysis TArgeting Chimera estrogen receptor degrader, in healthy adults

Aim To evaluate the effects of carbamazepine, a strong cytochrome P450 (CYP)3A4 inducer, on the pharmacokinetics and safety of vepdegestrant, a PROteolysis TArgeting Chimera estrogen receptor degrader. Methods This was a phase 1, open‐label, fixed‐sequence, two‐period study in healthy adult participants. During Period 1, a single oral dose of vepdegestrant 200 mg was administered (Day 1). During Period 2, carbamazepine dosing was titrated from 200 mg orally once daily (Days 1–3) to twice (Days 4–7) and three times daily (Days 8–19); a single oral dose of vepdegestrant 200 mg was administered (Day 14). Blood samples for pharmacokinetics analysis were collected up to 144 h after dosing in both periods. Safety was monitored throughout the study. Results Twelve healthy male participants were enrolled and treated. Following administration of vepdegestrant with (test) and without (reference) carbamazepine, test/reference ratios (90% confidence intervals) of the adjusted geometric means for vepdegestrant area under the plasma concentration–time curve from time 0 to infinity and maximum plasma concentration were 64.1% (60.0% to 68.4%) and 80.2% (74.0% to 86.8%), respectively. Similar decreases in ARV‐473 (vepdegestrant epimer) exposure were observed. Two participants discontinued during Period 2 due to elevated liver enzymes and maculopapular rash (both unrelated to vepdegestrant; one participant each). Conclusion Coadministration of multiple doses of carbamazepine 200 mg, a strong CYP3A4 inducer, with a single dose of vepdegestrant 200 mg resulted in a modest (36%) decrease in plasma vepdegestrant exposure. A single dose of vepdegestrant 200 mg was well tolerated in healthy adult participants. Clinical trial registration : NCT06005688.