Brilaroxazine Displays Limited Interaction with Clinically Relevant Drug Transporters

This is the authors' abstract. We don't add key points for this paper.

Abstract ID 129049 Poster Board 292 Background: Transporters influence drug absorption, distribution, and elimination, leading to pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs) with co-administered inhibitors and/or inducers. Drug regulators have recommended that sponsors evaluate their investigational drugs as substrates and/or inhibitors of clinically relevant transporters. Brilaroxazine, a D2/3/4 and 5-HT1A/2A partial agonist, a 5 HT2B/7 antagonist with binding affinity for 5-HT2B > D₂, and a mediator of inflammatory cytokines, offers a differentiated pharmacological and safety profile over other antipsychotics. Clinical trial experience established its efficacy, safety, and pharmacokinetic profile. Currently, brilaroxazine has completed phase 3 for schizophrenia. Methods: This in vitro study investigated this agent's interaction potential with clinically relevant drug transporters. P-gp and BCRP substrate/inhibitor studies involved Madin-Darby canine kidney (MDCKII) epithelial cells (Sigma-Aldrich, St. Louis, MO). OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K evaluation involved HEK293-derived human BSEP membrane vesicles, mock HEK-293 cells, and Corning® TransportoCell™ cryopreserved transporter cells (Corning Life Sciences, Bedford, MA). Brilaroxazine concentrations tested were 3, 10, and 30 μM. Standard inhibitors and positive controls used were specific to these transporters. Results: Brilaroxazine inhibited OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE2-K, BSEP, P-gp and BCRP with IC₅₀ values ranging from 5.7 mM to >100 mM. MATE1 was the only transporter with an IC₅₀ of <1 mM. Brilaroxazine showed defined concentration-dependent inhibitions with P-gp, BCRP, OATP1B1, OATP1B3, OAT3, OCT1, OCT2, MATE1, MATE2-K and BSEP, and a weak inhibition withOAT1. Brilaroxazine showed low to moderate permeability in MDR1-transfected MDCKII cell monolayers expressing P-gp at all concentration levels tested, with efflux ratios of 9.18, 3.54, and 1.71 at 3, 10 and 30 μM, respectively. P-gp inhibitor ketoconazole (50 μM) showed low permeability, with efflux ratios < 2 at all brilaroxazine concentrations. Brilaroxazine showed low to moderate permeability in BCRP-expressed MDCKII cell monolayers at all concentration levels tested, with efflux ratios of 4.33, 1.52, and 1.42 at 3, 10, and 30 μM, respectively. The BCRP inhibitor Ko-143 (10 μM) reduced brilaroxazine from 3 to 2.5 μM. All other transporter evaluations failed to demonstrate any significant evidence of substrate interactions. These included concentration-dependent inhibitions (OATP1B1, OATP1B3, OCT1 and OCT2), uptake activity vs. mock cells (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K), lack of inhibition by known blockers (MATE1, MATE2-K), ATP-dependent uptake with S/N ratios ∼1 (BSEP), and inhibition of activity in human hepatocytes BSEP). No differences appeared in all these evaluations vs. positive controls. Conclusions: Brilaroxazine did not interact with most transporters. It did not display substrate interactions with OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, or BSEP. Thus, one should not expect DDIs with inhibitors or inducers of these transporters. Brilaroxazine appears to be a defined P-gp and weak BCRP substrate. Co-administration with strong inhibitors or inducers of these transporters may affect systemic exposure, although such interactions need confirmation within the clinic. Reviva Pharmaceutical Holdings, Inc.