Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D610/10 Genotype in Healthy Japanese Men
Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safet...
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| Veröffentlicht in: | Journal of clinical pharmacology 2012-03, Vol.52 (3), p.388-403 |
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| creator | Matsui, A. Azuma, J. Witcher, J. W. Long, A. J. Sauer, J.-M. Smith, B. P. DeSante, K. A. Read, H. A. Takahashi, M. Nakano, M. |
| description | Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration–time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant. |
| doi_str_mv | 10.1177/0091270011398657 |
| format | Article |
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W. ; Long, A. J. ; Sauer, J.-M. ; Smith, B. P. ; DeSante, K. A. ; Read, H. A. ; Takahashi, M. ; Nakano, M.</creator><creatorcontrib>Matsui, A. ; Azuma, J. ; Witcher, J. W. ; Long, A. J. ; Sauer, J.-M. ; Smith, B. P. ; DeSante, K. A. ; Read, H. A. ; Takahashi, M. ; Nakano, M.</creatorcontrib><description>Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration–time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1177/0091270011398657</identifier><identifier>PMID: 21543662</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adrenergic Uptake Inhibitors - adverse effects ; Adrenergic Uptake Inhibitors - pharmacokinetics ; Adult ; Area Under Curve ; Asian Continental Ancestry Group - genetics ; atomoxetine ; Atomoxetine Hydrochloride ; Cultural differences ; CYP2D6 ; Cytochrome P-450 CYP2D6 - genetics ; Cytochrome P-450 CYP2D6 - metabolism ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Gene Expression Regulation, Enzymologic ; Genotype ; Genotype & phenotype ; Half-Life ; Humans ; Japanese ; Male ; Men ; pharmacokinetics ; Propylamines - adverse effects ; Propylamines - pharmacokinetics ; safety ; Young Adult</subject><ispartof>Journal of clinical pharmacology, 2012-03, Vol.52 (3), p.388-403</ispartof><rights>2012 American College of Clinical Pharmacology, Inc.</rights><rights>2012 American College of Clinical Pharmacology</rights><rights>2012 SAGE Publications</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6020-b2be34ba9b012978b172f2f2c3ca31795894e3844e3b28fa27b077ed6c5d21793</citedby><cites>FETCH-LOGICAL-c6020-b2be34ba9b012978b172f2f2c3ca31795894e3844e3b28fa27b077ed6c5d21793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1177%2F0091270011398657$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1177%2F0091270011398657$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21543662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matsui, A.</creatorcontrib><creatorcontrib>Azuma, J.</creatorcontrib><creatorcontrib>Witcher, J. W.</creatorcontrib><creatorcontrib>Long, A. J.</creatorcontrib><creatorcontrib>Sauer, J.-M.</creatorcontrib><creatorcontrib>Smith, B. P.</creatorcontrib><creatorcontrib>DeSante, K. A.</creatorcontrib><creatorcontrib>Read, H. A.</creatorcontrib><creatorcontrib>Takahashi, M.</creatorcontrib><creatorcontrib>Nakano, M.</creatorcontrib><title>Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D610/10 Genotype in Healthy Japanese Men</title><title>Journal of clinical pharmacology</title><addtitle>J Clin Pharmacol</addtitle><description>Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration–time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.</description><subject>Adrenergic Uptake Inhibitors - adverse effects</subject><subject>Adrenergic Uptake Inhibitors - pharmacokinetics</subject><subject>Adult</subject><subject>Area Under Curve</subject><subject>Asian Continental Ancestry Group - genetics</subject><subject>atomoxetine</subject><subject>Atomoxetine Hydrochloride</subject><subject>Cultural differences</subject><subject>CYP2D6</subject><subject>Cytochrome P-450 CYP2D6 - genetics</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Japanese</subject><subject>Male</subject><subject>Men</subject><subject>pharmacokinetics</subject><subject>Propylamines - adverse effects</subject><subject>Propylamines - pharmacokinetics</subject><subject>safety</subject><subject>Young Adult</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9v0zAUxyMEYmVw54QiceCysGc7tpPj1I12UzsKFCFOlpO-0KxJXGxXW_77OWuZ0CSELNuyvp_v8_sRRW8JfCREylOAnFAJQAjLM8Hls2hEOKdJKiB9Ho0GORn0o-iVczeBEyknL6MjSnjKhKCjyC_W2ra6NJu6Q1-X7iT-piv0_Umsu1W8NA1aXdRN7fvYVPGZN625C2CHD_pFVWHpB2X8c0HPBYFTAvEEO-P7LcZ1F09RN37dx1d6qzt0GM-xex29qHTj8M3hPo6-f7pYjqfJ7PPkcnw2S0oBFJKCFsjSQucFEJrLrCCSVmGVrNSMyJxneYosS8NR0KzSVBYgJa5EyVc06Ow4-rCPu7Xm9w6dV23tSmyakInZOZVTwSGjYiDfPyFvzM52ITlFJAgJjHEZKNhTpTXOWazU1tattr0ioIaBqKcDCZZ3h8C7osXVo-HPBAKQ7oFb03i0btPsbtGq9UPbQjyANMRLaGgBsPBKwiYQbOJgqxvs_5uHuhovpmnOWTAme6PTv_CvKv9dwIGvnce7x4-03SghmeTqx_VEfZ1df5lP5kvF2T2AV724</recordid><startdate>201203</startdate><enddate>201203</enddate><creator>Matsui, A.</creator><creator>Azuma, J.</creator><creator>Witcher, J. W.</creator><creator>Long, A. J.</creator><creator>Sauer, J.-M.</creator><creator>Smith, B. P.</creator><creator>DeSante, K. A.</creator><creator>Read, H. A.</creator><creator>Takahashi, M.</creator><creator>Nakano, M.</creator><general>Blackwell Publishing Ltd</general><general>SAGE Publications</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201203</creationdate><title>Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D610/10 Genotype in Healthy Japanese Men</title><author>Matsui, A. ; Azuma, J. ; Witcher, J. 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W.</au><au>Long, A. J.</au><au>Sauer, J.-M.</au><au>Smith, B. P.</au><au>DeSante, K. A.</au><au>Read, H. A.</au><au>Takahashi, M.</au><au>Nakano, M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D610/10 Genotype in Healthy Japanese Men</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>J Clin Pharmacol</addtitle><date>2012-03</date><risdate>2012</risdate><volume>52</volume><issue>3</issue><spage>388</spage><epage>403</epage><pages>388-403</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration–time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21543662</pmid><doi>10.1177/0091270011398657</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adrenergic Uptake Inhibitors - adverse effects Adrenergic Uptake Inhibitors - pharmacokinetics Adult Area Under Curve Asian Continental Ancestry Group - genetics atomoxetine Atomoxetine Hydrochloride Cultural differences CYP2D6 Cytochrome P-450 CYP2D6 - genetics Cytochrome P-450 CYP2D6 - metabolism Dose-Response Relationship, Drug Drug Administration Schedule Gene Expression Regulation, Enzymologic Genotype Genotype & phenotype Half-Life Humans Japanese Male Men pharmacokinetics Propylamines - adverse effects Propylamines - pharmacokinetics safety Young Adult |
| title | Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D610/10 Genotype in Healthy Japanese Men |
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