PII-109 - DRUG-DRUG INTERACTION (DDI) STUDY OF THE PROTEOLYSIS TARGETING CHIMERA (PROTAC) ANDROGEN RECEPTOR (AR) DEGRADER BAVDEGALUTAMIDE IN COMBINATION WITH THE P-GLYCOPROTEIN (P-GP) SUBSTRATE FEXOFENADINE IN HEALTHY MALE VOLUNTEERS.

J. Alicea, V. Patel, B. Ghent, V. Dai, T. Yu, J. Jiang; Arvinas Operations, Inc., New Haven, CT, USA.

Background: Bavdegalutamide (ARV-110) is a potent, selective, orally bioavailable, PROTAC AR degrader that is being developed for the treatment of prostate cancer. Bavdegalutamide 420 mg once daily has demonstrated an acceptable safety profile in ongoing clinical studies in men with prostate cancer. In vitro assessment indicated that bavdegalutamide has an inhibitory effect on P-gp and may potentially impact the pharmacokinetics (PK) of P-gp substrates such as fexofenadine. We evaluated the impact of a single dose of bavdegalutamide on the PK of a single dose of fexofenadine in healthy male volunteers. Safety also was evaluated.

Methods: In this phase 1, open-label, 2-period, fixed-sequence, DDI study, participants received a single oral dose of fexofenadine 60 mg in a fed state followed by a 7-day washout period. Participants then received a single oral dose of fexofenadine 60 mg with a single oral dose of bavdegalutamide 420 mg in the fed state. Blood samples for PK were collected up to 48 hours post dose. Primary endpoints were area under the curve from the time of dosing to time of last measurable concentration (AUC_last) and maximum plasma concentration (C_max) of fexofenadine. Secondary endpoints included additional PK parameters and adverse events (AEs).

Results: In total, 20 participants were enrolled (fexofenadine alone: n=20 for PK and safety populations; fexofenadine co-administered with bavdegalutamide: n=16, PK population and n=19, safety population). Co-administration of fexofenadine with bavdegalutamide resulted in a ≈2.8-fold higher AUC_last and ≈2.4-fold higher C_max of fexofenadine compared with fexofenadine alone (Table). Treatment-emergent AEs occurred in 17 (85%) participants and were all grade 1/2. Bavdegalutamide-related AEs were reported in 15 (79%) participants, with nausea being the most commonly reported in 10 (53%) participants. No AEs were considered related to fexofenadine.

Conclusion: Co-administration of bavdegalutamide with fexofenadine increased the extent of systemic exposure and the peak exposure of fexofenadine, suggesting that bavdegalutamide should not be co-administered with sensitive P-gp substrates in ongoing clinical studies. No safety concerns were identified with the study drugs when co-administered as single doses.