Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites

Abstract

The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)--dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (K = 1.0-2.8 nM), rat forebrain (K = 4.2 nM), and human platelets (K = 2.6-3.3 nM). Valbenazine (K = 110-190 nM) and NBI-136110 (K = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT, 5-HT, 5-HT) or dopamine (D or D) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].

Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

“…These are similar to the values observed with the non‐deuterated metabolites of tetrabenazine, with Ki values of 3.1 and 20 nM, respectively. Deuteration does not appear to cause a significant difference in the off‐target receptor binding profile compared with tetrabenazine; however, the affinity for other receptors is generally low, although one of the isomers of non‐deuterated β‐HTBZ has a Ki of 53 nM to the dopamine D2 receptor, as reported in the literature, and for which the clinical significance is unclear given the lack of a strong signal for parkinsonism in clinical trials of deutetrabenazine for TD…”

“…Deuteration does not appear to cause a significant difference in the off-target receptor binding profile compared with tetrabenazine; 34 however, the affinity for other receptors is generally low, although one of the isomers of non-deuterated β-HTBZ has a Ki of 53 nM to the dopamine D2 receptor, as reported in the literature, 45 and for which the clinical significance is unclear given the lack of a strong signal for parkinsonism in clinical trials of deutetrabenazine for TD. 1 were comparable or higher than tetrabenazine 25 mg but were associated with longer half-lives and lower maximum concentrations that occurred later.…”

Treatment of tardive dyskinesia with tetrabenazine or valbenazine: a systematic review

“…Valbenazine has two major metabolites: [+]-α-HTBZ (or R,R,R-HTBZ), which is formed by hydrolysis and is a common metabolite with tetrabenazine, and NBI-136110, which is formed by mono-oxidation. Studies have shown that these two metabolites have no affinity for other unintended targets [22]. This pharmacologic profile contributes to a lower potential for side effects and reduced concerns over pharmacokinetic drug interactions or the need to screen for CYP2D6 polymorphisms.…”

“…Valbenazine is a novel and highly selective VMAT2 inhibitor that is rapidly absorbed but more slowly metabolized, with a half-life of approximately 20 h that supports oncedaily dosing [22,26]. Valbenazine has two major metabolites: [+]-α-HTBZ (or R,R,R-HTBZ), which is formed by hydrolysis and is a common metabolite with tetrabenazine, and NBI-136110, which is formed by mono-oxidation.…”

“…Tetrabenazine binds selectively to VMAT2, but it is the dihydrotetrabenazine (HTBZ) metabolites that have the main pharmacologic effects. However, some of these metabolites (i.e., different HTBZ stereoisomers) have affinity for other off-target receptors [22], possibly contributing to unwanted side effects that can be dose-limiting and possibly confound treatment efforts [20,23,24]. In addition, due to its tolerability and pharmacokinetic profile, use of tetrabenazine for Huntington's disease includes recommendations for CYP2D6 genotyping to screen for poor metabolizer status when exceeding doses of 50 mg/day [15].…”