Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, α-HTBZ and β-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5.
In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine.
In vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites.
Adverse reactions associated with overdosage include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. In case of an overdose, general supportive and symptomatic measures are recommended while monitoring cardiac rhythm and vital signs. In managing overdosage, the possibility of multiple drug involvement should always be considered. No carcinogenicity studies were performed with deutetrabenazine. In p53+/– transgenic mice, there were no detectable tumors following oral administration of deutetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks. Findings from in vitro assays and in vivo mice micronucleus assay suggest that deutetrabenazine and its metabolites are unlikely to be mutagenic. The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of tetrabenazine had no effects on mating and reproductive systems of male and female rats.
IDENTIFICATION AND USE: Deutetrabenazine is used as adrenergic uptake inhibitor. It is is indicated for the treatment of chorea associated with Huntington's disease (HD) and tardive dyskinesia in adults. HUMAN STUDIES: Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a closely related vesicular monoamine transporter 2 (VMAT2) inhibitor. The following adverse reactions occurred with overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine. Deutetrabenazine may increase the risk for suicidality in patients with HD. Deutetrabenazine should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Deutetrabenazine and its deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites were negative in in vitro chromosome aberration assay in human peripheral blood lymphocytes in the presence or absence of metabolic activation. ANIMAL STUDIES: Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal development. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses. Deutetrabenazine and its deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites were negative in in vitro bacterial reverse mutation assay in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice.
Tetrabenazine has not been associated with rates of serum enzyme elevations greater than occur with placebo therapy, but information on liver test results during therapy is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation or dose modification have been reported by the sponsor. In prelicensure pivotal registration trials in several hundred patients, tetrabenazine was not associated with cases of jaundice or hepatitis. Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to tetrabenazine. Thus, clinically apparent liver injury with jaundice due to tetrabenazine must be rare, if it occurs at all.
Austedo is contraindicated in patients currently taking tetrabenazine or valbenazine. Austedo may be initiated the day following discontinuation of tetrabenazine
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
酒精或其它镇静药物的同时使用可能会产生累加效果，加剧镇静和嗜睡症状。
Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
The extent of absorption is 80% with oral deutetrabenazine. As deutetrabenazine is extensively metabolized to its main active metabolites following administration, linear dose dependence of peak plasma concentrations (Cmax) and AUC was observed for the metabolites after single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Cmax of deuterated α-HTBZ and β-HTBZ are reached within 3-4 hours post-dosing. Food may increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC.
Deutetrabenazine is mainly excreted in the urine as metabolites. In healthy subjects, about 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. α-HTBZ and β-HTBZ metabolites accounted for less than 10% of the administered dose in the urine.
The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex. Similar distribution pattern is expected for deutetrabenazine.
In patients with Huntington's disease, the median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively.
Results of PET-scan studies in humans show that following intravenous injection of (11)C-labeled tetrabenazine or alpha-dihydrotetrabenazine, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex.
Crystalline Forms of Benzoquinoline Inhibitors of Vesicular Monoamine Transporter 2
摘要：
本发明提供了Deutetrabenazine的晶型形式。本发明提供的特定晶型包括Deutetrabenazine Form APO-I，Deutetrabenazine和槲皮素的共晶，以及Deutetrabenazine Form APO-II，Deutetrabenazine和芦丁的共晶。还提供了包括Deutetrabenazine晶型形式的药物组合物，并且利用这些形式治疗与亨廷顿氏病相关的迟发性运动障碍和舞蹈症。
A novel process for the synthesis of tetrabenazine (1) and deutetrabenazine (2), two well-known drugs used for the treatment of chorea associated with Huntington’s disease, has been developed. All of the reaction parameters were optimized through a series of reactions and by using Design of Experiment techniques. The newly developed methods are industrially scalable and employ cheap, commercially available
Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
申请人：AUSPEX PHARMACEUTICALS, INC.
公开号：US11033540B2
公开（公告）日：2021-06-15
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
FORMULATIONS PHARMACOKINETICS OF DEUTERATED BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
申请人：Auspex Pharmaceuticals, Inc.
公开号：US20140336386A1
公开（公告）日：2014-11-13
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
FORMULATIONS AND PHARMACOKINETICS OF DEUTERATED BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
申请人：Auspex Pharmaceuticals, Inc.
公开号：US20150004231A1
公开（公告）日：2015-01-01
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
