PII-158 - THE EFFECT OF VEPDEGESTRANT, A PROTEOLYSIS TARGETING CHIMERA (PROTAC) ESTROGEN RECEPTOR (ER) DEGRADER, ON DABIGATRAN PHARMACOKINETICS (PK) IN HEALTHY ADULT PARTICIPANTS.

D. Yang¹, J. Winton², K. Matschke³, C. Kantaridis⁴, K. Lee², N. Chen⁵, Y. Zhang⁶, W. Tan¹; ¹Pfizer, Inc., San Diego, CA, USA, ²Pfizer, Inc., Groton, CT, USA, ³Pfizer, Inc., Collegeville, PA, USA, ⁴Pfizer, Inc., Brussels, Belgium, ⁵Pfizer, Inc., Beijing, China, ⁶Arvinas Operations, Inc., New Haven, CT, USA.

Background: The oral PROTAC ER degrader vepdegestrant (ARV-471) was well tolerated and had encouraging clinical activity in patients with ER+/human epidermal growth factor receptor 2- breast cancer in a first-in-human phase 1/2 study (NCT04072952). The objective of this study was to evaluate the impact of vepdegestrant on the PK of dabigatran etexilate (a model substrate for P-glycoprotein [P-gp]) in healthy adults (NCT05673889).

Methods: This was a phase 1, open-label, 2-period, fixed-sequence study in healthy male and female adults; female participants were of non-childbearing potential. In period 1, a single oral dose of dabigatran 75 mg was administered in a fed state. In period 2, a single oral dose of dabigatran 75 mg was administered about 90 minutes after a single oral dose of vepdegestrant 200 mg in a fed state. Serial blood PK samples were collected up to 48 h post-dabigatran dose.

Results: A total of 24 participants were enrolled and treated in this study. Co-administration of dabigatran with vepdegestrant increased the area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC_inf) and the maximum plasma concentration (C_max) of dabigatran by 98% and 92%, respectively (primary endpoints). The ratios of the adjusted geometric means (90% CI) for dabigatran AUC_inf and C_max were 197.81% (177.32%–220.66%) and 192.20% (166.56%–221.79%), respectively, following dabigatran+vepdegestrant (test) compared with dabigatran alone (reference). After dabigatran alone and after co-administration of dabigatran+vepdegestrant, treatment-emergent adverse events (TEAEs) occurred in 6 (25.0%) participants each. Treatment-related AEs occurred in 3 (12.5%) participants after dabigatran treatment (diarrhea, dry skin, hot flush, and nausea; 1 [4.2%] each) and in 1 (4.2%) participant after dabigatran+vepdegestrant (headache). All AEs were mild or moderate; no serious or severe AEs occurred and no discontinuations or dose modifications due to AEs were reported.

Conclusion: Co-administration of vepdegestrant increased dabigatran exposure, suggesting that vepdegestrant is a P-gp inhibitor. In ongoing clinical trials in patients with breast cancer, caution is recommended when using vepdegestrant with sensitive substrates of P-gp. The study treatments were well tolerated in healthy adults.