title: Analysis of CYP2D6 genotype and response to tetrabenazine.
abstract: Tetrabenazine is effective in the treatment of the chorea associated with Huntington disease and other hyperkinetic movement disorders. Following oral administration, tetrabenazine is hepatically transformed into 2 active metabolites that are CYP2D6 substrates. There are 4 CYP2D6 genotypes: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP2D6 genotyping was performed on sequential subjects treated with tetrabenazine, but results were not known at the time of titration. Duration of titration to a stable dose, total daily dose, response rating scores, and adverse events were retrospectively collected and subsequently analyzed. Of 127 patients, the majority (n = 100) were categorized as extensive metabolizers, 14 as intermediate metabolizers, 11 as poor metabolizers, and 2 as ultrarapid metabolizers. Ultrarapid metabolizer patients needed a longer titration (8 vs 3.3, 4.4, and 3 weeks, respectively; P < .01) to achieve optimal benefit and required a higher average daily dose than the other patients, but this difference did not reach statistical significance. The treatment response was less robust in the intermediate metabolizer group when compared with the extensive metabolizer patients (P = .013), but there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered.
authors.affiliation: Parkinson's Disease Center, Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Mehanna
authors.forename: Christine
authors.initials: C
authors.lastname: Hunter
authors.forename: Anthony
authors.initials: A
authors.lastname: Davidson
authors.forename: Joohi
authors.initials: J
authors.lastname: Jimenez-Shahed
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
mesh_terms: D000328:Adult; D018726:Anti-Dyskinesia Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics; D006948:Hyperkinesis / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders / Q000188:drug therapy* / Q000235:genetics*; D009207:Myoclonus / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics; D010641:Phenotype; D011595:Psychomotor Agitation / Q000188:drug therapy / Q000235:genetics; D013747:Tetrabenazine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005879:Tourette Syndrome / Q000188:drug therapy / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D018726:Anti-Dyskinesia Agents; D019389:Cytochrome P-450 CYP2D6; D013747:Tetrabenazine