Source: Health Products Regulatory Authority (IE) Revision Year: 2019 Publisher: Bausch Health Ireland Limited, 3013 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Other nervous system drugs
ATC Code: N07XX06
Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.
The precise mechanism by which tetrabenazine exerts its effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.
Studies conducted in vitro and in vivo have shown that tetrabenazine is a selective inhibitor of monoamine transportation into pre-synaptic neuronal vesicles, by reversible inhibition of the VMAT2 (vesicular monamine transporter 2), which is principally located in the central nervous system. Studies have shown that α-dihydrotetrabenazine, one of the principal metabolite of tetrabenazine, has a similar affinity and more significant selectivity for VMAT2.
At a synaptic level tetrabenazine and α-dihydrotetrabenazine creates a reversible depletion of monamines in the presynaptic terminals. Within the CNS tetrabenazine and α-dihydrotetrabenazine causes preferential depletion of dopamine from nerve terminals. Neurotransmitter depletion by a single dose of tetrabenazine is reversible and lasts only a few hours.
Tetrabenazine is quickly and mostly absorbed after oral administration. Its absorption is not affected by the taking of food.
Clinical testing has shown that a single oral dose of tetrabenazine undergoes extensive (>75%) absorption from the gastro-intestinal tract.
After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine to α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ and β-HTBZ are subsequently metabolized to another major circulating metabolite, O-dealkylated-HTBZ, for which Cmax is reached approximately 2 hours post-dosing.
The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.
The metabolism of tetrabenazine is complex, initially proceeding via the formation of alpha and beta dihydrotetrabenazine. α-HTBZ and β-HTBZ, major circulating metabolites, have half-lives of 4-8 hours and 2-4 hours, respectively. The majority of the observed metabolites appear to be formed from these dihydrotetrabenazines as a result of O-dealkylation, hydroxylation and conjugation.
After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. Clinical testing has shown that subjects with liver impairment have substantially reduced first-pass systemic metabolism of tetrabenazine, resulting in increased exposure to the parent compound compared to healthy subjects. The conversion of tetrabenazine to alpha and beta dihydrotetrabenazine appears to be slower in subjects with liver impairment as is the subsequent elimination of these metabolites.
No significant build-up has been observed after daily administration. The elimination half-life of dihydrotetrabenazine is approximately five hours. Tetrabenazine is mostly eliminated in metabolised form in urine (less than 2% of tetrabenazine is excreted in unchanged form).
After administration of single doses from 12.5 to 50 mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
In repeated dose toxicity studies orally administered tetrabenazine is generally well tolerated across all animal species tested. Most effects observed are related to the pharmacological parameters of the drug and reflect central monoamine depletion.
These signs typically include hypoactivity, lethargy, squinted eyes, or eyes closed. They last up to several hours after dosing and in some species at high doses interfere with normal food intake with consequent decreased or suppressed body weight gain. Across all animal species tested dose-dependent sedation is the dose limiting effect and the principal adverse effect following oral administration of tetrabenazine.
Tetrabenazine and metabolites α-HTBZ and β-HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. Tetrabenazine was negative in male mice and rats but equivocal in female rats in in vivo micronucleus tests.
Tetrabenazine did not cause an increase in any tumor type when administered for 26 weeks in the transgenic p53 heterozygous mouse model at doses up to 30 mg/kg/day. Tetrabenazine was non-carcinogenic when administered for 94 weeks to male rats at doses up to 12 mg/kg/day.
Tetrabenazine was not teratogenic to rats or rabbits at the maximum recommended human dose (MRHD) (3 or 13-fold, respectively). In prenatal/postnatal toxicity studies, tetrabenazine increased stillborn pups and neonatal mortality as well as delayed pup maturation in rats. These effects could either be indirect effects due to inadequate maternal care or a direct effect of tetrabenazine on the pups. The no-effect dose was 0.5 times the MRHD.
In a fertility and early embryonic development study at systemic exposures below clinical levels there was no effect on pregnancy or in utero survival in rats but estrous cycle length was increased and a delay in fertility was seen in female rats. Reproduction was unaffected in male rats.
Tetrabenazine and metabolites accumulate in melanin-containing tissues in partially pigmented rats. A single oral administration of 14C-tetrabenazine to Lister Hooded rats resulted in high levels of radioactivity that persisted in pigmented tissues (eye, uveal tract and pigmented fur) and were still measurable 21 days after administration while all other tissues were BLQ (Below Limit of Quantification).
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