In Vitro Pharmacologic Characteristics of Valbenazine (NBI-98854) and its Metabolites
This poster was presented at the 29th Annual U.S. Psychiatric & Mental Health Congress, held October 21-24, 2016, in San Antonio, Texas.
Valbenazine (NBI-98854), a novel compound that inhibits the vesicular monoamine transporter 2 (VMAT2), is currently in development for the treatment of tardive dyskinesia. Valbenazine has two major metabolites: (+)-α-dihydrotetrabenazine (DHTBZ) and a mono-oxy metabolite (NBI-136110). In vitro studies were performed to characterize the pharmacology of valbenazine and its metabolites. Radioligand binding studies were conducted to assess the ability of valbenazine and its metabolites to inhibit binding of [3H]-DHTBZ in rat striatum and human platelet homogenates. A broad panel screen was also conducted to test valbenazine and its metabolites for off-target interactions at more than 80 receptor, transporter, and ion channel sites. Radioligand binding studies showed that (+)-α-DHTBZ was a strong inhibitor of [3H]-DHTBZ binding in homogenates of rat striatum (Ki=1.0 to 2.8 nM), rat forebrain (Ki=4.2 nM), and human platelets (Ki=2.6 to 3.3 nM). Valbenazine and NBI-136110 also exhibited inhibitory effects on VMAT2, but to a lesser degree than (+)-α-DHTBZ (Ki=110 to 190 nM and Ki=160 to 220 nM respectively). Neither valbenazine nor (+)-α-DHTBZ exhibited any significant off-target interactions at serotonin (5 HT1A, 5-HT2A, 5 HT2B) or dopamine (D1-D4) receptor sites. These results indicate that valbenazine and (+)-α-DHTBZ inhibit VMAT2 selectively and specifically, without interactions at multiple receptor sites, suggesting the potential for fewer unwanted clinical side effects. In addition to being consistent with the favorable efficacy and tolerability results of recent clinical studies (KINECT 2 [NCT01733121], KINECT 3 [NCT02274558]), the pharmacologic characteristics of valbenazine and its metabolites suggest that this novel VMAT2 inhibitor may have therapeutic potential for various movement disorders.
