Pharmacy & Therapeutics - December 2008 - (Page 690)

DRUG FORECAST Tetrabenazine (Xenazine), An FDA-Approved Treatment Option For Huntington’s Disease–Related Chorea Tatiana Yero, PharmD, BS, and Jose A. Rey, PharmD, BCPP Key words: tetrabenazine, Xenazine, Huntington’s disease, chorea, Huntington’s chorea HD. Existing management strategies focus on improving symptoms and quality of life.4 Neuroleptic agents, including dopamine receptor blockers and presynaptic dopamine-depleting agents, have been used to control choreic movements.2 Until now, no medication had been approved in the U.S. for the treatment of chorea or any other symptom associated with HD. In August 2008, the FDA approved tetrabenazine (Xenazine) for this indication. In September 2008, Ovation Pharmaceuticals acquired the exclusive license in the U. S. to market this orphan drug from Prestwick Pharmaceuticals. Tetrabenazine has been used for decades in several countries to treat chorea and other hyperkinetic movement disorders, such as dystonias and tics.5 This article provides a concise review of the pharmacology, pharmacokinetics, safety, and efficacy of this much needed treatment option to ameliorate some of the disabling symptoms of HD. els of neurotransmitters inside the neuron and lower levels in the synaptic cleft, ensuring a gradual, regulated release across the plasma membrane. 7,8 The process also serves to protect the neurotransmitters from leakage or degradation by intraneuronal metabolism; in addition, the neuron is protected from the potential toxic effects of critically high levels of neurotransmitters.7,8 The vesicular monoamine transpor ter-2 (VMAT-2) is found mainly in the central nervous system (CNS) and in histaminergic cells of the adrenal medulla, blood cells, and stomach.7 The VMAT-2 transports serotonin, dopamine, norepinephrine, and histamine into vesicles for storage. Tetrabenazine acts primarily as a reversible high-affinity inhibitor of monoamine uptake into granular vesicles of presynaptic neurons by binding selectively to VMAT-2.9 As a result of this inhibition, monoamine degradation in the neuron is augmented, leading to depletion of the monoamines, particularly dopamine. 9 Studies have shown that tetrabenazine also blocks dopamine D2 receptors, but this affinity is 1,000-fold lower than its affinity for VMAT-2.10,11 It is unlikely that this mechanism is responsible for the therapeutic effects of this agent, but it might be involved with rarely reported acute dystonic reactions.12 The agent that is most similar to tetrabenazine and available in the U.S. is reserpine, which is also a monoamine depleter. Reserpine works by irreversibly inhibiting VMAT-1, in addition to VMAT2, in the periphery.5 This activity explains the higher frequency of drug-induced side effects such as hypotension and gastrointestinal pain and diarrhea. Tetrabenazine has a shorter half-life and a more rapid onset of action than reserpine, perhaps making it more beneficial in the clinical setting, because efficacy can be evaluated more quickly.5 INTRODUCTION Huntington’s disease (HD) is a progressive autosomal-dominant neuro degenerative disorder caused by 36 or more trinucleotide (CAG) repeats on the short arm of chromosome 4.1 The higher the number of repeats on the huntingtin gene, the more fully present the disorder. As a result of this abnormality, mutated huntingtin protein is formed and is a hallmark of HD. HD occurs worldwide in all ethnic groups but predominantly in Caucasian populations. 1 The prevalence rate in Europe and the U.S. is 4 to 8 per 100,000 individuals.2 In Japan, the prevalence is only 10% of this number.2 Symptoms generally appear between the ages of 35 and 40 but have been recorded as early as five years of age. These symptoms are devastating and disabling and involve movement disorders, incoordination, cognitive decline, personality and behavioral changes.1,2 The most striking and characteristic symptom is chorea, or involuntary dance-like movements that seem purposeless and abrupt. As the severity of symptoms progresses, patients are at a higher risk of dying because of complications, such as falls and aspiration. The typical period between diagnosis and death of the patient is 20 years.3 As of this writing, no treatment is available that can delay the progression of Dr. Yero is a Psychiatric Pharmacy Practice Resident and Dr. Rey is Associate Professor, both at Nova Southeastern University College of Pharmacy in the Pharmaceutical Sciences Department in Fort Lauderdale, Florida. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York, New York. CHEMICAL AND PHYSICAL PROPERTIES Tetrabenazine, an oral monoamine depleter, is a hexahydro-dimethoxy-benzoquinolizine derivative. A white to light yellow crystalline powder, it is sparingly soluble in water and soluble in ethanol. Scheduled to be launched by the end of 2008, it will be available as a cylindrical biplanar tablet with beveled edges in strengths of 12.5 mg (white) and 25 mg (yellow). The tablets should be stored at temperatures between 15˚ and 30˚C.6 MECHANISM OF ACTION The production of neurotransmitters occurs in neurons. These neurotransmitters are then stored in vesicles for later release.7 This results in higher levDisclosure: The authors have no financial or commercial relationships to disclose in regard to this article. 690 P&T® • December 2008 • Vol. 33 No. 12

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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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