Safety, Tolerability, and Pharmacokinetics of KNS‐760704 (Dexpramipexole) in Healthy Adult Subjects
Identifieur interne : 002F56 ( Main/Corpus ); précédent : 002F55; suivant : 002F57Safety, Tolerability, and Pharmacokinetics of KNS‐760704 (Dexpramipexole) in Healthy Adult Subjects
Auteurs : Bozik ; Mather ; Kramer ; Gribkoff ; IngersollSource :
- The Journal of Clinical Pharmacology [ 0091-2700 ] ; 2011-08.
English descriptors
- KwdEn :
Abstract
Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.
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DOI: 10.1177/0091270010379412
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ISTEX:FEE067F38142AF3ABB111BA526B84BCB961B9153Le document en format XML
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Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Dr Bozik MD</name><affiliations><json:string>Knopp Neurosciences, Pittsburgh, Pennsylvania</json:string></affiliations></json:item><json:item><name>Mr Mather BS</name><affiliations><json:string>Knopp Neurosciences, Pittsburgh, Pennsylvania</json:string></affiliations></json:item><json:item><name>Dr Kramer PhD</name><affiliations><json:string>Kramer Consulting LLC, North Potomac, Maryland</json:string></affiliations></json:item><json:item><name>Dr Gribkoff PhD</name><affiliations><json:string>Knopp Neurosciences, Pittsburgh, Pennsylvania</json:string></affiliations></json:item><json:item><name>Dr Ingersoll PhD</name><affiliations><json:string>Knopp Neurosciences, Pittsburgh, Pennsylvania</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>KNS‐760704</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dexpramipexole</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>(R)‐(+)‐pramipexole,(6R)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pharmacokinetics and drug metabolism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pharmaceutical research and development</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neurology</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>amyotrophic lateral sclerosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>motor neuron disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>safety</value></json:item></subject><articleId><json:string>JCPH5437</json:string></articleId><language><json:string>eng</json:string></language><abstract>Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. 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Ingersoll, PhD, Knopp Neurosciences Inc., 2100 Wharton Street, Suite 615, Pittsburgh, PA 15203 e‐mail: .</p></note><affiliation>Knopp Neurosciences, Pittsburgh, Pennsylvania</affiliation></author></analytic><monogr><title level="j">The Journal of Clinical Pharmacology</title><idno type="pISSN">0091-2700</idno><idno type="eISSN">1552-4604</idno><idno type="DOI">10.1002/(ISSN)1552-4604</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2011-08"></date><biblScope unit="volume">51</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1177">1177</biblScope><biblScope unit="page" to="1185">1185</biblScope></imprint></monogr><idno type="istex">FEE067F38142AF3ABB111BA526B84BCB961B9153</idno><idno type="DOI">10.1177/0091270010379412</idno><idno type="ArticleID">JCPH5437</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>KNS‐760704</term></item><item><term>dexpramipexole</term></item><item><term>(R)‐(+)‐pramipexole,(6R)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine</term></item><item><term>pharmacokinetics and drug metabolism</term></item><item><term>pharmaceutical research and development</term></item><item><term>neurology</term></item><item><term>amyotrophic lateral sclerosis</term></item><item><term>motor neuron disease</term></item><item><term>safety</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2011-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/FEE067F38142AF3ABB111BA526B84BCB961B9153/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1002/(ISSN)1552-4604</doi><issn type="print">0091-2700</issn><issn type="electronic">1552-4604</issn><idGroup><id type="product" value="JCPH"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="JOURNAL OF CLINICAL PHARMACOLOGY">The Journal of Clinical Pharmacology</title></titleGroup></publicationMeta><publicationMeta level="part" position="08108"><doi origin="wiley">10.1002/jcph.2011.51.issue-8</doi><numberingGroup><numbering type="journalVolume" number="51">51</numbering><numbering type="journalIssue" number="8">8</numbering></numberingGroup><coverDate startDate="2011-08">August 2011</coverDate></publicationMeta><publicationMeta level="unit" type="miscellaneous" position="4" status="forIssue"><doi origin="wiley">10.1177/0091270010379412</doi><idGroup><id type="unit" value="JCPH5437"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="tocHeading1">Pharmacokinetics</title></titleGroup><copyright>2011 American College of Clinical Pharmacology</copyright><eventGroup><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:3.2.0 mode:FullText" date="2013-03-07"></event><event type="firstOnline" date="2013-03-07"></event><event type="publishedOnlineFinalForm" date="2013-03-07"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-30"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="1177">1177</numbering><numbering type="pageLast" number="1185">1185</numbering></numberingGroup><correspondenceTo> Address for correspondence: Evan W. Ingersoll, PhD, Knopp Neurosciences Inc., 2100 Wharton Street, Suite 615, Pittsburgh, PA 15203 e‐mail: <email normalForm="eingersoll@knoppneuro-sciences.com">eingersoll@knoppneuro‐sciences.com</email>.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JCPH.JCPH5437.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Revised version accepted June 21, 2010</unparsedEditorialHistory><countGroup><count type="referenceTotal" number="37"></count><count type="linksCrossRef" number="58"></count><count type="figureTotal" number="4"></count><count type="tableTotal" number="3"></count><count type="formulaTotal" number="0"></count></countGroup><titleGroup><title type="main">Safety, Tolerability, and Pharmacokinetics of KNS‐760704 (Dexpramipexole) in Healthy Adult Subjects</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><honorifics>Dr</honorifics><givenNames>Michael E.</givenNames><familyName>Bozik</familyName><degrees>MD</degrees></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><honorifics>Mr</honorifics><givenNames>James L.</givenNames><familyName>Mather</familyName><degrees>BS</degrees></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a2"><personName><honorifics>Dr</honorifics><givenNames>William G.</givenNames><familyName>Kramer</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1"><personName><honorifics>Dr</honorifics><givenNames>Valentin K.</givenNames><familyName>Gribkoff</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1" corresponding="yes"><personName><honorifics>Dr</honorifics><givenNames>Evan W.</givenNames><familyName>Ingersoll</familyName><degrees>PhD</degrees></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="US"><unparsedAffiliation>Knopp Neurosciences, Pittsburgh, Pennsylvania</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="US"><unparsedAffiliation>Kramer Consulting LLC, North Potomac, Maryland</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">KNS‐760704</keyword><keyword xml:id="k2">dexpramipexole</keyword><keyword xml:id="k3">(R)‐(+)‐pramipexole,(6R)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine</keyword><keyword xml:id="k4">pharmacokinetics and drug metabolism</keyword><keyword xml:id="k5">pharmaceutical research and development</keyword><keyword xml:id="k6">neurology</keyword><keyword xml:id="k7">amyotrophic lateral sclerosis</keyword><keyword xml:id="k8">motor neuron disease</keyword><keyword xml:id="k9">safety</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><p>Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Safety, Tolerability, and Pharmacokinetics of KNS‐760704 (Dexpramipexole) in Healthy Adult Subjects</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Safety, Tolerability, and Pharmacokinetics of KNS‐760704 (Dexpramipexole) in Healthy Adult Subjects</title></titleInfo><name type="personal"><namePart type="termsOfAddress">Dr</namePart><namePart type="family">Bozik</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Knopp Neurosciences, Pittsburgh, Pennsylvania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Mr</namePart><namePart type="family">Mather</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Knopp Neurosciences, Pittsburgh, Pennsylvania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr</namePart><namePart type="family">Kramer</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Kramer Consulting LLC, North Potomac, Maryland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr</namePart><namePart type="family">Gribkoff</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Knopp Neurosciences, Pittsburgh, Pennsylvania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="termsOfAddress">Dr</namePart><namePart type="family">Ingersoll</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Knopp Neurosciences, Pittsburgh, Pennsylvania</affiliation><description>Correspondence: Address for correspondence: Evan W. Ingersoll, PhD, Knopp Neurosciences Inc., 2100 Wharton Street, Suite 615, Pittsburgh, PA 15203 e‐mail: .</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="miscellaneous"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2011-08</dateIssued><edition>Revised version accepted June 21, 2010</edition><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="tables">3</extent><extent unit="references">37</extent></physicalDescription><abstract lang="en">Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.</abstract><subject lang="en"><genre>Keywords</genre><topic>KNS‐760704</topic><topic>dexpramipexole</topic><topic>(R)‐(+)‐pramipexole,(6R)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine</topic><topic>pharmacokinetics and drug metabolism</topic><topic>pharmaceutical research and development</topic><topic>neurology</topic><topic>amyotrophic lateral sclerosis</topic><topic>motor neuron disease</topic><topic>safety</topic></subject><relatedItem type="host"><titleInfo><title>The Journal of Clinical Pharmacology</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0091-2700</identifier><identifier type="eISSN">1552-4604</identifier><identifier type="DOI">10.1002/(ISSN)1552-4604</identifier><identifier type="PublisherID">JCPH</identifier><part><date>2011</date><detail type="volume"><caption>vol.</caption><number>51</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>1177</start><end>1185</end><total>9</total></extent></part></relatedItem><identifier type="istex">FEE067F38142AF3ABB111BA526B84BCB961B9153</identifier><identifier type="DOI">10.1177/0091270010379412</identifier><identifier type="ArticleID">JCPH5437</identifier><accessCondition type="use and reproduction" contentType="copyright">2011 American College of Clinical Pharmacology</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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