Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: AOP Orphan Pharmaceuticals AG, Wilhelminenstrasse 91/II f, 1160 Vienna, Austria
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.
Animal studies have shown that tetrabenazine disturbs the metabolism of biogenic amines, for instance that of serotonin and noradrenaline, and that this activity is limited to the brain. The supposition is that this effect of tetrabenazine on amines in the brain explains the clinical effects in the brain.
Tetrabenazine inhibits the re-uptake of monoamines in the neuroterminal of the presynaptic neurons of the central nervous system. This results in a depletion of monoamines, including dopamine. Dopamine depletion results in hypokinesis leading to a reduction in chorea severity.
Tetrabenazine inhibits the re-uptake of monoamines in synaptic nerve terminals by a reversible and short-term binding to the vesicular monoamine transporter (VMAT). VMAT2 transports monoamines especially in peripheral and central neurons, while VMAT1 regulates the transport in peripheral chromaffine tissues. Tetrabenazine has a higher affinity for VMAT2 than for VMAT1. Thus, tetrabenazine has a short, hardly peripheral effect.
Tetrabenazine is quickly and completely absorbed after oral administration. Its absorption is not affected by the intake of food.
Clinical testing has shown that a single dose of tetrabenazine undergoes extensive absorption (≥75%) from the gastro-intestinal tract.
Plasma levels of tetrabenazine decline rapidly, with a half-life of 1.9 hours.
Tetrabenazine has a low and erratic bioavailability (4.9% to 6%). It appears to be extensively metabolised by first-pass metabolism. Major metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (ß-HTBZ) are formed by reduction.
Primary metabolites α-HTBZ and ß-HTBZ are mainly metabolised by cytochrome P450 2D6 liver enzyme. CYP2D6 inhibitors may increase the plasma concentration of these metabolites.
Tetrabenazine is mostly eliminated in metabolised form in urine (only 2.1% of tetrabenazine is excreted unchanged in the urine).
After administration of single doses from 12.5 to 50 mg mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.
Mild and moderate hepatic impairment increases the exposure and prolongs the half-lives of tetrabenazine and hydroxytetrabenazine (data in 4 patients with Child Pugh score 5-6 and 1 patient with Child Pugh score 9). Severe hepatic impairment has not been studied.
In repeat-dose toxicity studies, the effects observed with orally administered tetrabenazine were related to depletion of central stores of monoamines. Common symptoms were hypoactivity, lethargy, strabismus, or closed eyes. Primarily pharmacological effects such as sedation were observed and considered dose limiting.
The genotoxic potential of tetrabenazine has been studied using a series of conventional tests. In vitro, tetrabenazine was negative for point mutations and positive for chromosomal aberrations in chinese hamster ovary cells, at cytotoxic concentrations only. Tetrabenazine was not genotoxic in an in vivo chromosomal aberration test; however, carcinogenicity studies have not been performed.
In a fertility and early embryonic development study at systemic exposures below those observed clinically there was no evidence of effect on pregnancy or in utero survival in rats. Length of the estrous cycle was increased and a delay in fertility was seen in female rats. Reproduction was unaffected in male rats.
Tetrabenazine was not embryotoxic or teratogenic in the rabbit; however, the observed systemic exposure was lower than that observed clinically. The potential embryotoxic and teratogenic effects were also insufficiently studied in the rat. In a peri/postnatal study in the rat, increased neonatal mortality was observed, the cause of which is unknown.
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