Analysis of CYP2D6 genotype and response to tetrabenazine.
Identifieur interne : 000B04 ( Main/Exploration ); précédent : 000B03; suivant : 000B05Analysis of CYP2D6 genotype and response to tetrabenazine.
Auteurs : Raja Mehanna [États-Unis] ; Christine Hunter ; Anthony Davidson ; Joohi Jimenez-Shahed ; Joseph Jankovic [États-Unis]Source :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2013.
English descriptors
- KwdEn :
- Adult, Anti-Dyskinesia Agents (adverse effects), Anti-Dyskinesia Agents (pharmacokinetics), Anti-Dyskinesia Agents (therapeutic use), Cytochrome P-450 CYP2D6 (genetics), Female, Genotype, Humans, Huntington Disease (drug therapy), Huntington Disease (genetics), Hyperkinesis (drug therapy), Hyperkinesis (genetics), Male, Middle Aged, Movement Disorders (drug therapy), Movement Disorders (genetics), Myoclonus (drug therapy), Myoclonus (genetics), Pharmacogenetics, Phenotype, Psychomotor Agitation (drug therapy), Psychomotor Agitation (genetics), Tetrabenazine (adverse effects), Tetrabenazine (pharmacokinetics), Tetrabenazine (therapeutic use), Tourette Syndrome (drug therapy), Tourette Syndrome (genetics), Treatment Outcome.
- MESH :
- chemical , adverse effects : Anti-Dyskinesia Agents, Tetrabenazine.
- chemical , genetics : Cytochrome P-450 CYP2D6.
- chemical , pharmacokinetics : Anti-Dyskinesia Agents, Tetrabenazine.
- chemical , therapeutic use : Anti-Dyskinesia Agents, Tetrabenazine.
- drug therapy : Huntington Disease, Hyperkinesis, Movement Disorders, Myoclonus, Psychomotor Agitation, Tourette Syndrome.
- genetics : Huntington Disease, Hyperkinesis, Movement Disorders, Myoclonus, Psychomotor Agitation, Tourette Syndrome.
- Adult, Female, Genotype, Humans, Male, Middle Aged, Pharmacogenetics, Phenotype, Treatment Outcome.
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.
DOI: 10.1002/mds.25278
PubMed: 23280482
Affiliations:
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last="Davidson">Anthony Davidson</name></author><author><name sortKey="Jimenez Shahed, Joohi" sort="Jimenez Shahed, Joohi" uniqKey="Jimenez Shahed J" first="Joohi" last="Jimenez-Shahed">Joohi Jimenez-Shahed</name></author><author><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name><affiliation><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university" n="3">Baylor College of Medicine</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2013">2013</date><idno type="doi">10.1002/mds.25278</idno><idno type="RBID">pubmed:23280482</idno><idno type="pmid">23280482</idno><idno type="wicri:Area/PubMed/Corpus">000B23</idno><idno type="wicri:Area/PubMed/Curation">000B23</idno><idno type="wicri:Area/PubMed/Checkpoint">000B18</idno><idno 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77030</wicri:noRegion></affiliation></author><author><name sortKey="Hunter, Christine" sort="Hunter, Christine" uniqKey="Hunter C" first="Christine" last="Hunter">Christine Hunter</name></author><author><name sortKey="Davidson, Anthony" sort="Davidson, Anthony" uniqKey="Davidson A" first="Anthony" last="Davidson">Anthony Davidson</name></author><author><name sortKey="Jimenez Shahed, Joohi" sort="Jimenez Shahed, Joohi" uniqKey="Jimenez Shahed J" first="Joohi" last="Jimenez-Shahed">Joohi Jimenez-Shahed</name></author><author><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name><affiliation><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university" n="3">Baylor College of Medicine</orgName></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Anti-Dyskinesia Agents (adverse effects)</term><term>Anti-Dyskinesia Agents (pharmacokinetics)</term><term>Anti-Dyskinesia Agents (therapeutic use)</term><term>Cytochrome P-450 CYP2D6 (genetics)</term><term>Female</term><term>Genotype</term><term>Humans</term><term>Huntington Disease (drug therapy)</term><term>Huntington Disease (genetics)</term><term>Hyperkinesis (drug therapy)</term><term>Hyperkinesis (genetics)</term><term>Male</term><term>Middle Aged</term><term>Movement Disorders (drug therapy)</term><term>Movement Disorders (genetics)</term><term>Myoclonus (drug therapy)</term><term>Myoclonus (genetics)</term><term>Pharmacogenetics</term><term>Phenotype</term><term>Psychomotor Agitation (drug therapy)</term><term>Psychomotor Agitation (genetics)</term><term>Tetrabenazine (adverse effects)</term><term>Tetrabenazine (pharmacokinetics)</term><term>Tetrabenazine (therapeutic use)</term><term>Tourette Syndrome (drug therapy)</term><term>Tourette Syndrome (genetics)</term><term>Treatment Outcome</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Anti-Dyskinesia Agents</term><term>Tetrabenazine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Cytochrome P-450 CYP2D6</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Anti-Dyskinesia Agents</term><term>Tetrabenazine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Anti-Dyskinesia Agents</term><term>Tetrabenazine</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Huntington Disease</term><term>Hyperkinesis</term><term>Movement Disorders</term><term>Myoclonus</term><term>Psychomotor Agitation</term><term>Tourette Syndrome</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Huntington Disease</term><term>Hyperkinesis</term><term>Movement Disorders</term><term>Myoclonus</term><term>Psychomotor Agitation</term><term>Tourette Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Female</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Pharmacogenetics</term><term>Phenotype</term><term>Treatment Outcome</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Texas</li></region><settlement><li>Houston</li></settlement><orgName><li>Baylor College of Medicine</li></orgName></list><tree><noCountry><name sortKey="Davidson, Anthony" sort="Davidson, Anthony" uniqKey="Davidson A" first="Anthony" last="Davidson">Anthony Davidson</name><name sortKey="Hunter, Christine" sort="Hunter, Christine" uniqKey="Hunter C" first="Christine" last="Hunter">Christine Hunter</name><name sortKey="Jimenez Shahed, Joohi" sort="Jimenez Shahed, Joohi" uniqKey="Jimenez Shahed J" first="Joohi" last="Jimenez-Shahed">Joohi Jimenez-Shahed</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Mehanna, Raja" sort="Mehanna, Raja" uniqKey="Mehanna R" first="Raja" last="Mehanna">Raja Mehanna</name></noRegion><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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