Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]‐α‐HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]‐α‐deuHTBZ, [+]‐β‐deuHTBZ, [−]‐α‐deuHTBZ, and [−]‐β‐deuHTBZ. An open‐label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off‐target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]‐α‐HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off‐target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [−]‐α‐deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D2S, D3) and serotonin (5‐HT1A, 5‐HT2B, 5‐HT7) receptors. [+]‐β‐deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half‐life of [+]‐α‐HTBZ (22.2 hours) was ∼3× longer than that of [+]‐β‐deuHTBZ (7.7 hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off‐target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off‐target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites.

IntroductionTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with dopamine receptor blocking agents (eg, antipsychotics). Valbenazine is a highly selective vesicular monoamine transporter 2 inhibitor with several safe and effective dosing options now approved for once-daily (QD) treatment of TD in adults. Valbenazine 80 mg QD is the recommended dose for TD; however, 40 or 60 mg QD (newly approved dose) may be considered depending on response and tolerability. The recent approval of valbenazine 60 mg was based on results from an analysis that used the FDA’s model-informed drug development (MIDD) approach and leveraged existing data from the 6-week, phase 3 registration trial of valbenazine (KINECT 3).MethodsA population pharmacokinetic (popPK) model was developed to describe plasma concentration-time profiles for valbenazine and its primary active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). An exposure-response (E-R) model was developed using the area under the concentration-time curve (AUC) of [+]-α-HTBZ (exposure) and change from baseline in the Abnormal Involuntary Movement Scale total score (AIMS-CFB) (response). Stepwise E-R model development evaluated various linear and nonlinear models to describe AIMS-CFB vs [+]-α-HTBZ AUC and time. E-R relationships established with the 40 and 80 mg data were used to predict AIMS-CFB for a 60 mg dose up to week 6, accounting for study-to-study, inter-individual, and residual variabilities.ResultsSteady-state valbenazine and [+]-α-HTBZ concentrations were well described by a joint parent-metabolite popPK model. An Emax model with asymptotic exponential delay in the maximal valbenazine effect adequately characterized the E-R relationship between AIMS-CFB and [+]-α-HTBZ AUC. The simulated confidence intervals of response were consistent with the observed KINECT 3 results, demonstrating the utility of the model to predict efficacy results. The established E-R model was subsequently used to predict AIMS-CFB for valbenazine 60 mg QD at week 6. Mean AIMS scores decreased (improved) in a dose-dependent manner, with 60 mg QD predicted to result in least-squares mean (SEM) AIMS-CFB of −2.7 0.4, which is between the reported AIMS-CFB for 40 mg (−1.9 ± 0.4) and 80 mg (−3.2 ± 0.4). All simulated trials demonstrated valbenazine 60 mg to be significantly superior to placebo in AIMS-CFB after 6 weeks of treatment.ConclusionsThis analysis integrated and leveraged data from two previously approved valbenazine doses (40 and 80 mg QD) using an MIDD approach. The results provided key evidence that an intermediate dose (newly approved 60 mg QD) could be considered therapeutically beneficial without the need for an additional clinical trial. The availability of a valbenazine 60 mg dose to complement the previously approved doses fills an existing medical need for patients with TD who could benefit from this third effective dose.FundingNeurocrine Biosciences, Inc.