Pharmacy & Therapeutics - December 2008 - (Page 691)

DRUG FORECAST PHARMACOKINETICS Absorption and Distribution The pharmacokinetic properties of tetrabenazine are summarized in Table 1.6,9,13 Oral absorption of tetrabenazine is at least 75%. In trials, administration of food following a single dose had no effect on mean peak plasma levels (Cmax) or on the area-under-the-curve (AUC) concentration; therefore, tetrabenazine may be given without regard to food intake.6 Tetrabenazine displays a relatively low bioavailability of 0.049 ± 0.032.13 It is rapidly metabolized hepatically into two compounds: alpha- and beta-dihydrotetrabenazine (HTBZ). The alpha-HTBZ metabolite is active, whereas the betaHTBZ metabolite is chemically inert. Because of the drug’s rapid metabolism, plasma concentrations of tetrabenazine are generally below the limit of detection. The Cmax of both alpha-HTBZ and beta-HTBZ is reached within 1.5 hours after dosing.6 Both forms of HTBZ are then further metabolized into another major metabolite, O-dealkylated-HTBZ. The Cmax for this compound is reached in two hours after the dose is given.6 In contrast to the parent compound, both forms of HTBZ have a high bioavailability and are less protein-bound (44% to 59%) than tetrabenazine (83% to 88%). 13 Plasma levels of HTBZ are higher than those of tetrabenazine.13,14 Both compounds follow linear kinetics in the dosage range that was studied, which was 37.5 mg to 112.5 mg/day.15 Results of positron emission tomography (PET) scans, as indicated by the manufacturer, report that radioactivity was rapidly distributed to the brain following an intravenous (IV) injection of radiolabeled tetrabenazine, with the most binding occurring in the striatum and the least binding in the cortex.6 dose.6 The remainder of the dose found in the urine consists of other circulating metabolites and products of oxidative metabolism.6 DOSAGE Adults. The dose of tetrabenazine should be individualized, and a medication guide should be included with the prescription for each patient.6 The starting dose should be 12.5 mg/day once in the morning. After one week, the dose should be increased to 12.5 mg twice daily; it should then be titrated up slowly by 12.5 mg at weekly intervals to identify the lowest and best tolerated effective dose. If a dose of 37.5 to 50 mg/day is needed, it should be given in three divided doses. Each dose should not exceed 25 mg. Patients who seem to require doses greater than 50 mg/day should undergo genotyping for CYP 2D6. Doses above 100 mg/day are not recommended for any patient.6 Tapering of the tetrabenazine dose is not needed when the drug is being discontinued. Chorea may become evident within 12 to 18 hours after the last dose.6 After a treatment interruption of more than five days, dosing should be retitrated. However, if treatment is interrupted for less than five days, the previous maintenance dose can be resumed with no titration.6 Extensive or intermediate metabolizers of CYP 2D6. At doses above 50 Metabolism and Elimination Tetrabenazine displays a variable halflife among individual patients. 13 The half-life of the parent compound is 10 hours.13,14 The alpha-HTBZ metabolite has a half-life of four to eight hours, and the beta-HTBZ’s half-life is two to four hours.6 Given these short half-lives, the drug should be taken two to three times daily. In addition, efficacy may be accurately evaluated within days.9 The alpha-HTBZ and beta-HTBZ metabolites are formed by carbonyl reductase, which occurs primarily in the liver. These compounds are then further metabolized, mainly by cytochrome P450 2D6, with some contribution by CYP 1A2.6 Tetrabenazine and its metabolites are not likely to result in any significant inhibition or induction of CYP enzymes, and they are not likely to be substrates or inhibitors of P-glycoprotein.6 Elimination of tetrabenazine and its metabolites is primarily renal. In six healthy volunteers, approximately 75% of the tetrabenazine dose was excreted in the urine; fecal elimination accounted for approximately 7% to 16% of the dose.6 No unchanged tetrabenazine has been isolated in human urine. The urinary excretion of alpha-HTBZ and beta-HTBZ accounted for less than 10% of the given Table 1 Pharmacokinetic Properties of Tetrabenazine (Xenazine) Tetrabenazine Absorption and distribution Oral bioavailability Protein binding Metabolism and elimination Mean half-life Primary metabolic pathway Secondary metabolic pathway Excretion 0.049 ± 0.032 83%–88% 10 hours CYP 2D6 Carbonyl reductase Renal, 75% Fecal, 7%–16% HTBZ — 44%–59% alpha-HTBZ, 4–8 hours beta-HTBZ, 2–4 hours CYP 2D6 CYP 1A2 (minimal) — — CYP = cytochrome; HTBZ = dihydrotetrabenazine. Data from Xenazine (tetrabenazine), product information;6 Kenney C, et al. Exp Rev Neurother 2006;6(1):7–17;9 and Roberts MS, et al. Eur J Clin Pharmacol 1986;29:703–708.13 mg/day, tetrabenazine should still be titrated up slowly by 12.5 mg at weekly inter vals. The higher doses should be divided into three daily doses. The maximum recommended daily dose is 100 mg, and the maximum single dose in this group is 37.5 mg.6 Poor metabolizers of CYP 2D6. The dosing of tetrabenazine is similar to that for patients who are extensive metabolizers. For poor metabolizers, however, the maximum single dose is 25 mg and the maximum recommended daily dosage is 50 mg.6 Elderly patients. No controlled studies have been per formed in elderly adults. Hepatically impaired patients. The manufacturer reports a study in which the effects of tetrabenazine in hepatic impairment were compared with its effects on healthy patients. Twelve patients with mild-to-moderate chronic liver im- Vol. 33 No. 12 • December 2008 • P&T® 691

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Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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