The precise mechanism by which tetrabenazine exerts its anti-chorea 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. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α- and β-HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).
QTc Prolongation: The effect of a single 25 or 50 mg dose of tetrabenazine on the QT interval was studied in a randomized, double-blind, placebo controlled crossover study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, tetrabenazine caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of tetrabenazine does not further increase the effect on the QTc interval. Effects at higher exposures to either tetrabenazine or its metabolites have not been evaluated (see PRECAUTIONS - QTc Prolongation).
Melanin Binding: Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.
Absorption and Distribution: Following oral administration of tetrabenazine, the extent of absorption is at least 75%. 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 effects of food on the bioavailability of tetrabenazine were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ. XENAZINE can therefore be administered without regard to meals.
Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.
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%.
Metabolism and Excretion: α-HTBZ and β-HTBZ, major circulating metabolites, have half-lives of 4-8 hours and 2-4 hours, respectively. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2. β-HTBZ is O-dealkylated principally by CYP2D6.
After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. O-dealkylated HTBZ, α-HTBZ, and β-HTBZ are the major circulating metabolites, and they are subsequently metabolized to sulfate or glucuronide conjugates. CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP2E1 do not play a major role in metabolism of α-HTBZ or β-HTBZ based on in vitro studies.
The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. Their effect on CYP2B6 has not been evaluated. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
Neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.
Excretion: After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
The pharmacokinetics of tetrabenazine and its primary metabolites have not been studied in pediatric subjects.
The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.
There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
Racial differences in the pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied.
The effect of renal insufficiency on the pharmacokinetics of tetrabenazine and its primary metabolites has not been studied.
The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmax in hepatically impaired subjects was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment (see CONTRAINDICATIONS; PRECAUTIONS - Use in Patients with Concomitant Illness; and DOSAGE AND ADMINISTRATION).
CYP2D6 Poor Metabolizers
Although the pharmacokinetics of tetrabenazine and its metabolites in subjects who do not express the drug metabolizing enzyme CYP2D6 (poor metabolizers, PMs) have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased compared to subjects who express the enzyme (extensive metabolizers, EMs), with an increase similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively) (see PRECAUTIONS - Drug Interactions and DOSAGE AND ADMINISTRATION). Patients should be genotyped for CYP2D6 prior to treatment with daily doses of tetrabenazine over 50 mg (see WARNINGS - Laboratory Tests). Patients who are PMs should not be given daily doses greater than 50 mg (see DOSAGE AND ADMINISTRATION).
α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. A strong CYP2D6 inhibitor (paroxetine) markedly increases exposure to these metabolites (see PRECAUTIONS - Drug Interactions).
Digoxin: Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that tetrabenazine (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors.