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.