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1.
Expert Rev Neurother ; 24(9): 849-863, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38982802

RESUMO

INTRODUCTION: Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID). AREAS COVERED: The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER. EXPERT OPINION: Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.


Assuntos
Preparações de Ação Retardada , Doença de Huntington , Discinesia Tardia , Tetrabenazina , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/complicações , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Tetrabenazina/administração & dosagem , Tetrabenazina/farmacocinética , Tetrabenazina/efeitos adversos , Coreia/tratamento farmacológico , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/uso terapêutico , Inibidores da Captação Adrenérgica/farmacocinética , Inibidores da Captação Adrenérgica/efeitos adversos , Comprimidos
2.
J Clin Psychopharmacol ; 44(4): 386-396, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38901008

RESUMO

BACKGROUND: Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. METHODS: Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline. RESULTS: Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05). CONCLUSIONS: Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.


Assuntos
Antagonistas de Dopamina , Discinesia Tardia , Tetrabenazina , Humanos , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/induzido quimicamente , Masculino , Feminino , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/efeitos adversos , Tetrabenazina/administração & dosagem , Pessoa de Meia-Idade , Adulto , Antagonistas de Dopamina/efeitos adversos , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Idoso , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagem , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento
3.
J Clin Psychopharmacol ; 44(4): 353-361, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38767901

RESUMO

PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.


Assuntos
Discinesia Tardia , Tetrabenazina , Valina , Humanos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Discinesia Tardia/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Valina/análogos & derivados , Valina/administração & dosagem , Valina/farmacologia , Valina/efeitos adversos , Idoso , Resultado do Tratamento , Adulto , Escala de Movimento Involuntário Anormal , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagem
4.
J Psychopharmacol ; 38(6): 562-566, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38641957

RESUMO

BACKGROUND: Valbenazine is used for tardive movement disorders in adults. Current studies on its safety are mostly from clinical trials and small case reports, limiting information on rare adverse reactions. This study investigated valbenazine-related adverse event (AE) risk signals using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Valbenazine AEs data were collected from the FAERS database from 2017 Q2 to 2023 Q1, employing methods like reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network, and empirical Bayesian geometric mean. RESULTS: After data cleaning and drug screening, there were 20,837 AEs primarily suspecting valbenazine, involving 26 system organ classes and 125 AEs related to valbenazine at the preferred terms level. AEs related to valbenazine were mainly concentrated in nervous system disorders, general disorders and administration site conditions, and psychiatric disorders. Eye disorders and gastrointestinal disorders are new AEs not labeled in the valbenazine instructions. In addition, some new potential AE signals were found, such as Tardive dyskinesia and eyelid function disorder. CONCLUSION: The common AEs of valbenazine in the real world are consistent with the instructions, but there are some newly discovered suspicious AEs.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Tetrabenazina , United States Food and Drug Administration , Valina , Tetrabenazina/análogos & derivados , Tetrabenazina/efeitos adversos , Humanos , Estados Unidos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Valina/análogos & derivados , Valina/efeitos adversos , Bases de Dados Factuais , Mineração de Dados/métodos , Discinesia Tardia/induzido quimicamente , Masculino , Teorema de Bayes , Adulto
5.
Artigo em Inglês | MEDLINE | ID: mdl-38497033

RESUMO

Background: Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population. Methods: We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects. Results: An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated. Discussion: The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality. Conclusion: The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.


Assuntos
Discinesia Tardia , Tetrabenazina , Valina , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/induzido quimicamente , Tetrabenazina/efeitos adversos , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina
6.
Mov Disord ; 39(5): 847-854, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38477228

RESUMO

BACKGROUND: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18F-9-fluoropropyldihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). OBJECTIVE: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using 18F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. METHODS: We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using 18F-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. RESULTS: VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. CONCLUSIONS: Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. © 2024 International Parkinson and Movement Disorder Society.


Assuntos
Corpo Estriado , Doença de Parkinson , Paralisia Supranuclear Progressiva , Proteínas Vesiculares de Transporte de Monoamina , Humanos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tetrabenazina/análogos & derivados , Substância Negra/diagnóstico por imagem , Substância Negra/metabolismo , Substância Negra/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos
7.
J Clin Psychopharmacol ; 44(2): 107-116, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38421921

RESUMO

PURPOSE: This post hoc analysis investigated whether a patient's underlying psychiatric disease (schizophrenia/schizoaffective disorder [SCHZ] or bipolar disorder/depressive disorder [MOOD]) influenced the efficacy or safety of valbenazine for tardive dyskinesia (TD) in an Asian population. METHODS: We analyzed data from J-KINECT, a multicenter, phase II/III, randomized, double-blind study, which consisted of a 6-week placebo-controlled period followed by a 42-week extension where Japanese patients with TD received once-daily 40- or 80-mg valbenazine. We compared the change from baseline in Abnormal Involuntary Movement Scale total score and Clinical Global Impression of TD score between patients with SCHZ and those with MOOD, and incidence of treatment-emergent adverse events. RESULTS: Of 256 patients included in the placebo-controlled period, 211 continued to the long-term extension. The mean change from baseline in Abnormal Involuntary Movement Scale total score at week 6 (95% confidence interval) was -1.8 (-3.2 to -0.5) and -3.3 (-4.7 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (SCHZ group), and -2.4 (-3.9 to -0.9) and -3.5 (-5.1 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (MOOD group), demonstrating improvement at either dose level over placebo, regardless of the underlying disease. These results were maintained to week 48, and improvements of Clinical Global Impression of TD scores were similar. There were no notable differences in the incidence of serious or fatal treatment-emergent adverse events by underlying disease; differences in the incidence of worsening schizophrenia and depression were attributed to underlying disease progression. CONCLUSIONS: Safety and efficacy of long-term valbenazine therapy for TD did not vary according to underlying psychiatric disease.


Assuntos
Antipsicóticos , Transtorno Bipolar , Transtorno Depressivo , Transtornos Psicóticos , Esquizofrenia , Discinesia Tardia , Tetrabenazina , Valina , Humanos , Antipsicóticos/efeitos adversos , Transtorno Bipolar/induzido quimicamente , Transtorno Depressivo/tratamento farmacológico , Japão , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/complicações , Discinesia Tardia/induzido quimicamente , Tetrabenazina/análogos & derivados , Valina/análogos & derivados
8.
Eur J Nucl Med Mol Imaging ; 51(8): 2271-2282, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38393375

RESUMO

PURPOSE: Dynamic total-body imaging enables new perspectives to investigate the potential relationship between the central and peripheral regions. Employing uEXPLORER dynamic [11C]CFT PET/CT imaging with voxel-wise simplified reference tissue model (SRTM) kinetic modeling and semi-quantitative measures, we explored how the correlation pattern between nigrostriatal and digestive regions differed between the healthy participants as controls (HC) and patients with Parkinson's disease (PD). METHODS: Eleven participants (six HCs and five PDs) underwent 75-min dynamic [11C]CFT scans on a total-body PET/CT scanner (uEXPLORER, United Imaging Healthcare) were retrospectively enrolled. Time activity curves for four nigrostriatal nuclei (caudate, putamen, pallidum, and substantia nigra) and three digestive organs (pancreas, stomach, and duodenum) were obtained. Total-body parametric images of relative transporter rate constant (R1) and distribution volume ratio (DVR) were generated using the SRTM with occipital lobe as the reference tissue and a linear regression with spatial-constraint algorithm. Standardized uptake value ratio (SUVR) at early (1-3 min, SUVREP) and late (60-75 min, SUVRLP) phases were calculated as the semi-quantitative substitutes for R1 and DVR, respectively. RESULTS: Significant differences in estimates between the HC and PD groups were identified in DVR and SUVRLP of putamen (DVR: 4.82 ± 1.58 vs. 2.58 ± 0.53; SUVRLP: 4.65 ± 1.36 vs. 2.84 ± 0.67; for HC and PD, respectively, both p < 0.05) and SUVREP of stomach (1.12 ± 0.27 vs. 2.27 ± 0.65 for HC and PD, respectively; p < 0.01). In the HC group, negative correlations were observed between stomach and substantia nigra in both the R1 and SUVREP values (r=-0.83, p < 0.05 for R1; r=-0.94, p < 0.01 for SUVREP). Positive correlations were identified between pancreas and putamen in both DVR and SUVRLP values (r = 0.94, p < 0.01 for DVR; r = 1.00, p < 0.001 for SUVRLP). By contrast, in the PD group, no correlations were found between the aforementioned target nigrostriatal and digestive areas. CONCLUSIONS: The parametric images of R1 and DVR generated from the SRTM model, along with SUVREP and SUVRLP, were proposed to quantify dynamic total-body [11C]CFT PET/CT in HC and PD groups. The distinction in correlation patterns of nigrostriatal and digestive regions between HC and PD groups identified by R1 and DVR, or SUVRs, may provide new insights into the disease mechanism.


Assuntos
Doença de Parkinson , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Feminino , Pessoa de Meia-Idade , Idoso , Substância Negra/diagnóstico por imagem , Substância Negra/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinética , Imagem Corporal Total/métodos , Estudos de Casos e Controles , Radioisótopos de Carbono
9.
Clin Pharmacol Drug Dev ; 13(3): 224-232, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38214040

RESUMO

Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once-daily (test) and twice-daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24 mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7 days. Plasma concentrations were collected on Days 4-6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α-dihydrotetrabenazine (α-HTBZ) and ß-dihydrotetrabenazine (ß-HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration-time curve over 24 hours at steady state (AUC0-24 h,ss ) and for maximum plasma concentrations at steady state (Cmax,ss ). The GMRs for AUC0-24 h,ss were 115% for deutetrabenazine and 95% for deuterated total (α+ß)-HTBZ; and the GMR for Cmax,ss for deutetrabenazine was 95%. Relative bioavailability was assessed for Cmax,ss of the active metabolites; the GMR was 78% for total (α+ß)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and Cmax, and the active metabolites were bioequivalent with regard to AUC0-24 h,ss .


Assuntos
Doença de Huntington , Tetrabenazina/análogos & derivados , Humanos , Adulto , Equivalência Terapêutica , Comprimidos , Disponibilidade Biológica
10.
Neurol Sci ; 45(5): 2047-2055, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-37973627

RESUMO

BACKGROUND: Huntington's disease (HD) is a rare progressive neurological disorder, and telemedicine has the potential to improve the quality of care for patients with HD. Deutetrabenazine (DTBZ) can reduce chorea symptoms in HD; however, there is limited experience with this medication in Asian countries. METHODS: Retrospective and prospective studies were employed to explore the feasibility and reliability of a video-based telemedicine system for HD patient care. Reliability was demonstrated through consistency between selected-item scores (SIS) and total motor scores (TMS) and the agreement of scores obtained from hospital and home videos. Finally, a single-centre real-world DTBZ management study was conducted based on the telemedicine system to explore the efficacy of DTBZ in patients with HD. RESULTS: There were 77 patients included in the retrospective study, and a strong correlation was found between SIS and TMS (r = 0.911, P < 0.0001), indicating good representativeness. There were 32 patients enrolled in the prospective study. The reliability was further confirmed, indicated by correlations between SIS and TMS (r = 0.964, P < 0.0001) and consistency of SIS derived from the in-person and virtual visits (r = 0.969, P < 0.0001). There were 17 patients included in the DTBZ study with a mean 1.41 (95% confidence interval, 0.37-2.46) improvement in chorea score and reported treatment success. CONCLUSIONS: A video-based telemedicine system is a feasible and reliable option for HD patient care. It may also be used for drug management as a supplementary tool for clinical visits.


Assuntos
Coreia , Doença de Huntington , Telemedicina , Tetrabenazina/análogos & derivados , Humanos , Doença de Huntington/complicações , Doença de Huntington/tratamento farmacológico , Coreia/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Reprodutibilidade dos Testes
13.
Future Med Chem ; 14(13): 991-1003, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35638444

RESUMO

Aim: To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Method: Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with 1H-1H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. The VMAT2 affinity of the stereoisomers, inhibition in vivo and pharmacokinetics in rats were evaluated. Results: Three stereoisomers were obtained: P1, P2 and P3, and all had similar VMAT2 binding modes. P2 [(2R, 3R, 11bR)-13a] showed the highest potential VMAT2 binding activity (Ki = 0.75 nM), decreased locomotor activity in rats and had an oral absolute bioavailability of 92.0%. Conclusion: P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.


Assuntos
Moduladores de Transporte de Membrana/farmacologia , Tetrabenazina , Proteínas Vesiculares de Transporte de Monoamina , Animais , Simulação de Acoplamento Molecular , Ratos , Estereoisomerismo , Tetrabenazina/análogos & derivados , Tetrabenazina/química , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
14.
Parkinsonism Relat Disord ; 97: 47-51, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35299070

RESUMO

INTRODUCTION: Deutetrabenazine is approved by the US Food and Drug Administration to treat tardive dyskinesia (TD) based on 2 pivotal, 12-week, placebo-controlled studies (ARM-TD and AIM-TD) evaluating safety and efficacy in patients with baseline total motor Abnormal Involuntary Movement Scale (AIMS) score ≥6. This analysis estimated the minimal clinically important change (MCIC) in total motor AIMS score in TD patients treated with deutetrabenazine. METHODS: The pooled analysis population included all patients in ARM-TD and AIM-TD who received study drug and had ≥1 postbaseline AIMS assessment. MCIC analyses were performed using Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors. MCIC was defined as the mean change from baseline in total motor AIMS score in patients treated with deutetrabenazine who were rated minimally improved on PGIC or CGIC at Week 12. RESULTS: This analysis included 295 patients (deutetrabenazine, n = 197; placebo, n = 98). At Week 12, the MCIC in deutetrabenazine-treated patients was -2.4 based on the PGIC and -2.1 based on the CGIC. Mean change from baseline in total motor AIMS score for placebo-treated patients rated minimally improved was -1.4 based on the PGIC and -1.5 based on the CGIC. The proportion of deutetrabenazine-treated patients who achieved improvement in total motor AIMS score by ≥2 and ≥3 points was 66% and 55%, respectively. CONCLUSION: Using anchor-based methodology, the MCIC on the AIMS for deutetrabenazine in patients with TD was approximately -2, suggesting that a reduction in total motor AIMS score of ∼2 is associated with clinically meaningful improvement in TD symptoms.


Assuntos
Antipsicóticos , Discinesia Tardia , Escala de Movimento Involuntário Anormal , Antipsicóticos/uso terapêutico , Humanos , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico
16.
Eur J Clin Pharmacol ; 78(1): 11-18, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34491372

RESUMO

PURPOSE: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and ß-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites. METHODS: In this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4-12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1-4 and 11-14. Paroxetine trough concentrations were obtained pre-dose on days 9-13. Safety examinations occurred throughout the study. RESULTS: Paroxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0-∞) and ß-HTBZ (2.1-fold Cmax and 5.6-fold AUC0-∞), and correspondingly, 1.6-fold Cmax and threefold AUC0-∞ for total (α + ß)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine). CONCLUSIONS: Paroxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacologia , Paroxetina/farmacologia , Tetrabenazina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/farmacocinética , Adulto , Área Sob a Curva , Citocromo P-450 CYP2D6/metabolismo , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Tetrabenazina/farmacocinética
17.
Am J Geriatr Psychiatry ; 30(3): 360-371, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34511333

RESUMO

OBJECTIVES: To assess long-term safety and efficacy of deutetrabenazine in younger (<55 years) and older (≥55 years) adult participants with tardive dyskinesia (TD). DESIGN: Three-year, single-arm, open-label extension (OLE) study enrolling participants who completed the 12-week, pivotal ARM-TD or AIM-TD studies. SETTING: Seventy-six centers in the United States and Europe. PARTICIPANTS: A total of 337 participants with TD (119 younger and 218 older). INTERVENTION: Deutetrabenazine was initiated at 12 mg/day and titrated once weekly by 6 mg/day using a response-driven dosing regimen until adequate dyskinesia control was reached or a clinically significant adverse event occurred. MEASUREMENTS: This post hoc analysis assessed change and percent change from baseline in total motor Abnormal Involuntary Movement Scale (AIMS) score, response rates for ≥50% AIMS improvement, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), and safety in younger and older participants with TD. RESULTS: After 3 years of open-label treatment, mean deutetrabenazine dose was ∼39.5 mg/day in both groups. Mean±SE changes from baseline in total motor AIMS score were -6.7 ± 0.62 and -6.5 ± 0.47 in younger and older participants, respectively (percent changes: -61.4% ± 4.10% and -54.6% ± 3.01%); 76% of younger and 62% of older participants achieved ≥50% AIMS response. Most younger and older participants achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%). Deutetrabenazine was generally well tolerated in both groups. CONCLUSIONS: Deutetrabenazine treatment was associated with sustained improvements in total motor AIMS score, treatment success, and improved quality of life, and was well tolerated in younger and older adults with TD in this 3-year OLE study.


Assuntos
Discinesia Tardia , Tetrabenazina , Inibidores da Captação Adrenérgica/efeitos adversos , Idoso , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/complicações , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/efeitos adversos , Tetrabenazina/análogos & derivados , Resultado do Tratamento
18.
JAMA Netw Open ; 4(10): e2128204, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34609495

RESUMO

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults. Objective: To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents. Design, Setting, and Participants: This phase 2/3, randomized, double-masked, placebo-controlled, parallel-group, dose-titration study included children and adolescents (aged 6-16 years) with Tourette syndrome with active tics causing distress or impairment (ie, Yale Global Tic Severity Scale-Total Tic Score [YGTSS-TTS] ≥20). The trial was conducted over 12 weeks, with 1 week of follow-up from February 2018 to November 2019 at 36 centers in the United States, Canada, Denmark, Russia, Serbia, and Spain. Data analysis was conducted from January 31 to April 22, 2020. Intervention: Patients were randomized (1:1) to receive deutetrabenazine or placebo, titrated during 7 weeks to an optimal level, followed by a 5-week maintenance period. The maximum total daily deutetrabenazine dose was 48 mg/d. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 12 in YGTSS-TTS. Key secondary end points included changes in Tourette Syndrome-Clinical Global Impression, Tourette Syndrome-Patient Global Impression of Impact, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety was assessed based on treatment-emergent adverse events, vital signs, questionnaires, and laboratory parameters. Results: A total of 119 participants were randomized to deutetrabenazine (59 participants; mean [SD] age, 11.5 [2.5] years; 53 [90%] boys; 49 [83%] White; 3 [5%] Black) and placebo (60 participants; mean [SD] age, 11.5 [2.6] years; 51 [85%] boys; 53 [88%] White; 3 [5%] Black). At week 12, the difference in YGTSS-TTS score was not significant between deutetrabenazine and placebo (least squares mean difference, -0.7; 95% CI, -4.1 to 2.8; P = .69; Cohen d, -0.07). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 38 patients (66%) and 33 patients (56%) receiving deutetrabenazine and placebo, respectively, and were generally mild or moderate. Conclusions and Relevance: In this study of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. These results may be informative for future studies of treatments for tics in Tourette syndrome. Trial Registration: ClinicalTrials.gov Identifier: NCT03452943.


Assuntos
Segurança do Paciente/normas , Tetrabenazina/análogos & derivados , Síndrome de Tourette/tratamento farmacológico , Resultado do Tratamento , Adolescente , Comportamento do Adolescente/psicologia , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Segurança do Paciente/estatística & dados numéricos , Tetrabenazina/administração & dosagem , Tetrabenazina/normas , Síndrome de Tourette/psicologia
19.
JAMA Netw Open ; 4(10): e2129397, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34661664

RESUMO

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. Conclusions and Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.


Assuntos
Tetrabenazina/análogos & derivados , Síndrome de Tourette/tratamento farmacológico , Adolescente , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pediatria/métodos , Pediatria/estatística & dados numéricos , Tetrabenazina/administração & dosagem , Tetrabenazina/uso terapêutico , Tiques/tratamento farmacológico , Resultado do Tratamento
20.
Eur J Med Chem ; 224: 113718, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329999

RESUMO

Vesicular monoamine transporter 2 (VMAT2) is essential for synaptic transmission of all biogenic amines in the brain including serotonin, norepinephrine, histamine, and dopamine (DA). Given its crucial role in the neurophysiology and pharmacology of the central nervous system, VMAT2 is recognized as an important therapeutic target for various neurological disorders such as tardive dyskinesia (TD). Here, a novel series of dihydrotetrabenazine derivative analogs were designed and synthesized to evaluate their effects on [3H]dihydrotetrabenazine (DTBZ) binding and [3H]DA uptake at VMAT2. Of these analogs, compound 13e showed a high binding affinity for VMAT2 (IC50 = 5.13 ± 0.16 nM) with excellent inhibition of [3H]DA uptake (IC50 = 6.04 ± 0.03 nM) in striatal synaptosomes. In human liver microsomes, 13e was more stable (T1/2 = 161.2 min) than other reported VMAT2 inhibitors such as DTBZ (T1/2 = 119.5 min). In addition, 13e effectively inhibited the spontaneous locomotor activity (percent inhibition at 3 µmol/kg = 64.7%) in Sprague-Dawley rats. Taken together, our results indicate that 13e might be a promising lead compound for the development of novel treatments of TD.


Assuntos
Tetrabenazina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Humanos , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico
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