Effect of esomeprazole on the pharmacokinetics of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader, in healthy participants

AIMS: The aim of this study is to evaluate the effects of multiple doses of esomeprazole, a strong proton pump inhibitor and acid-reducing agent, on the pharmacokinetics and safety of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader. METHODS: This was a Phase 1, open-label, two-period, crossover, single-dose study in healthy adult participants. During Period 1, on Day 1, a single oral dose of vepdegestrant 200 mg was administered with a moderate-fat meal following overnight fasting. During Period 2, esomeprazole 40 mg was administered once daily on Days 1-5; a single dose of vepdegestrant 200 mg was given with a moderate-fat meal on Day 5 following esomeprazole 40 mg. Serial blood samples for vepdegestrant pharmacokinetics and safety laboratory analyses were collected predose and up to 168 h after vepdegestrant dosing in each period. Safety was monitored throughout the study. RESULTS: Twelve participants were enrolled and treated. Following administration of vepdegestrant with (test) and without (reference) esomeprazole, test/reference ratios (90% CIs) of the adjusted geometric means for vepdegestrant area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration were 83.73% (76.32, 91.86) and 74.11% (63.47, 86.52), respectively. Similar decreases in ARV-473 (vepdegestrant epimer) plasma exposure were observed. All 12 treatment-emergent adverse events experienced by seven participants were mild in severity. CONCLUSION: Coadministration of multiple daily doses of esomeprazole 40 mg with vepdegestrant 200 mg under fed conditions in healthy adult participants resulted in mild decreases in vepdegestrant plasma exposure. Vepdegestrant 200 mg was well tolerated in healthy adult participants.