Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans
The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of mye...
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| Veröffentlicht in: | Drug metabolism and disposition 2010-11, Vol.38 (11), p.2023-2031 |
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| creator | SHILLING, Adam D NEDZA, Frank M SHEPARD, Stacey RODGERS, James YUE, Tai-Yuen YELESWARAM, Swamy EMM, Thomas DIAMOND, Sharon MCKEEVER, Edward PUNWANI, Naresh WILLIAMS, William ARVANITIS, Argyrios GALYA, Laurine G MEI LI |
| description | The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [(14)C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration 70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low ( |
| doi_str_mv | 10.1124/dmd.110.033787 |
| format | Article |
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INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t(1/2) of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono- and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.</description><identifier>ISSN: 0090-9556</identifier><identifier>EISSN: 1521-009X</identifier><identifier>DOI: 10.1124/dmd.110.033787</identifier><identifier>PMID: 20699411</identifier><identifier>CODEN: DMDSAI</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Biological and medical sciences ; Chromatography, High Pressure Liquid ; Dose-Response Relationship, Drug ; Double-Blind Method ; Enzyme Inhibitors - blood ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - urine ; Feces - chemistry ; Female ; General pharmacology ; Humans ; Janus Kinase 1 - antagonists & inhibitors ; Janus Kinase 2 - antagonists & inhibitors ; Male ; Medical sciences ; Metabolic Clearance Rate ; Molecular Structure ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; Pharmacology. Drug treatments ; Pyrazoles - blood ; Pyrazoles - metabolism ; Pyrazoles - pharmacokinetics ; Pyrazoles - urine ; Tandem Mass Spectrometry</subject><ispartof>Drug metabolism and disposition, 2010-11, Vol.38 (11), p.2023-2031</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-2df54e0cc3f2e6eba6d6e202cf6715358ac72f7d1747182079382b1af71bf6523</citedby><cites>FETCH-LOGICAL-c390t-2df54e0cc3f2e6eba6d6e202cf6715358ac72f7d1747182079382b1af71bf6523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23386726$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20699411$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SHILLING, Adam D</creatorcontrib><creatorcontrib>NEDZA, Frank M</creatorcontrib><creatorcontrib>SHEPARD, Stacey</creatorcontrib><creatorcontrib>RODGERS, James</creatorcontrib><creatorcontrib>YUE, Tai-Yuen</creatorcontrib><creatorcontrib>YELESWARAM, Swamy</creatorcontrib><creatorcontrib>EMM, Thomas</creatorcontrib><creatorcontrib>DIAMOND, Sharon</creatorcontrib><creatorcontrib>MCKEEVER, Edward</creatorcontrib><creatorcontrib>PUNWANI, Naresh</creatorcontrib><creatorcontrib>WILLIAMS, William</creatorcontrib><creatorcontrib>ARVANITIS, Argyrios</creatorcontrib><creatorcontrib>GALYA, Laurine G</creatorcontrib><creatorcontrib>MEI LI</creatorcontrib><title>Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans</title><title>Drug metabolism and disposition</title><addtitle>Drug Metab Dispos</addtitle><description>The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [(14)C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t(1/2) of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono- and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.</description><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Enzyme Inhibitors - blood</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - urine</subject><subject>Feces - chemistry</subject><subject>Female</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>Janus Kinase 1 - antagonists & inhibitors</subject><subject>Janus Kinase 2 - antagonists & inhibitors</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic Clearance Rate</subject><subject>Molecular Structure</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrazoles - blood</subject><subject>Pyrazoles - metabolism</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - urine</subject><subject>Tandem Mass Spectrometry</subject><issn>0090-9556</issn><issn>1521-009X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtLAzEURoMoWh9bl5KNu07NTTLJzFJLtdX6ACsIIkMmk9BoJ1MmU1F_vZH6WN2Py_kul4PQIZABAOUnVV3FQAaEMZnJDdSDlEJCSP64iXpxkCRPU7GDdkN4IQQ4Z_k22qFE5DkH6KHPa9Opslm4UPfx6F23pnON72PlK3w3V22tdPPqfNzqgBuLn4APnyc3wzMCGac8gvjeLIzu3JvBl8qvAp59tE2IFXzlvAoGwwnFEz93peuato-dx-NVrXzYR1tWLYI5-Jl76OF8NBuOk-ntxWR4Ok00y0mX0Mqm3BCtmaVGmFKJShhKqLZCQsrSTGlJraxAcgkZJTJnGS1BWQmlFSlle2iwvqvjX6E1tli2rlbtRwGk-JZYRIkxkGItMRaO1oXlqqxN9Yf_WovA8Q-gglYL2yqvXfjnGMuEpIJ9AU4_eEc</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>SHILLING, Adam D</creator><creator>NEDZA, Frank M</creator><creator>SHEPARD, Stacey</creator><creator>RODGERS, James</creator><creator>YUE, Tai-Yuen</creator><creator>YELESWARAM, Swamy</creator><creator>EMM, Thomas</creator><creator>DIAMOND, Sharon</creator><creator>MCKEEVER, Edward</creator><creator>PUNWANI, Naresh</creator><creator>WILLIAMS, William</creator><creator>ARVANITIS, Argyrios</creator><creator>GALYA, Laurine G</creator><creator>MEI LI</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>IQODW</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></search><sort><creationdate>20101101</creationdate><title>Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans</title><author>SHILLING, Adam D ; NEDZA, Frank M ; SHEPARD, Stacey ; RODGERS, James ; YUE, Tai-Yuen ; YELESWARAM, Swamy ; EMM, Thomas ; DIAMOND, Sharon ; MCKEEVER, Edward ; PUNWANI, Naresh ; WILLIAMS, William ; ARVANITIS, Argyrios ; GALYA, Laurine G ; MEI LI</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-2df54e0cc3f2e6eba6d6e202cf6715358ac72f7d1747182079382b1af71bf6523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Biological and medical sciences</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Enzyme Inhibitors - blood</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - urine</topic><topic>Feces - chemistry</topic><topic>Female</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>Janus Kinase 1 - antagonists & inhibitors</topic><topic>Janus Kinase 2 - antagonists & inhibitors</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic Clearance Rate</topic><topic>Molecular Structure</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrazoles - blood</topic><topic>Pyrazoles - metabolism</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - urine</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SHILLING, Adam D</creatorcontrib><creatorcontrib>NEDZA, Frank M</creatorcontrib><creatorcontrib>SHEPARD, Stacey</creatorcontrib><creatorcontrib>RODGERS, James</creatorcontrib><creatorcontrib>YUE, Tai-Yuen</creatorcontrib><creatorcontrib>YELESWARAM, Swamy</creatorcontrib><creatorcontrib>EMM, Thomas</creatorcontrib><creatorcontrib>DIAMOND, Sharon</creatorcontrib><creatorcontrib>MCKEEVER, Edward</creatorcontrib><creatorcontrib>PUNWANI, Naresh</creatorcontrib><creatorcontrib>WILLIAMS, William</creatorcontrib><creatorcontrib>ARVANITIS, Argyrios</creatorcontrib><creatorcontrib>GALYA, Laurine G</creatorcontrib><creatorcontrib>MEI LI</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Drug metabolism and disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SHILLING, Adam D</au><au>NEDZA, Frank M</au><au>SHEPARD, Stacey</au><au>RODGERS, James</au><au>YUE, Tai-Yuen</au><au>YELESWARAM, Swamy</au><au>EMM, Thomas</au><au>DIAMOND, Sharon</au><au>MCKEEVER, Edward</au><au>PUNWANI, Naresh</au><au>WILLIAMS, William</au><au>ARVANITIS, Argyrios</au><au>GALYA, Laurine G</au><au>MEI LI</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans</atitle><jtitle>Drug metabolism and disposition</jtitle><addtitle>Drug Metab Dispos</addtitle><date>2010-11-01</date><risdate>2010</risdate><volume>38</volume><issue>11</issue><spage>2023</spage><epage>2031</epage><pages>2023-2031</pages><issn>0090-9556</issn><eissn>1521-009X</eissn><coden>DMDSAI</coden><abstract>The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [(14)C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration <1 h), declining in a monophasic or biphasic fashion (mean t(1/2) of 2.32 and 5.81 h, respectively). Recovery of administered radioactivity was fairly rapid (>70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low (<50% of parent). Two metabolite peaks in plasma (M18 and a peak containing M16/M27, both hydroxylations on the cyclopentyl moiety) were identified as major (30 and 14% of parent based on area under the curve from 0 to 24 h). The exposures of other circulating INCB018424-related peaks were <10% of parent, consisting of mono- and dihydroxylated metabolites. The profiles in urine and feces consisted of hydroxyl and oxo metabolites and subsequent glucuronide conjugates with parent drug accounting for <1% of the excreted dose, strongly suggesting that after an oral dose, INCB018424 was >95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>20699411</pmid><doi>10.1124/dmd.110.033787</doi><tpages>9</tpages></addata></record> |
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| ispartof | Drug metabolism and disposition, 2010-11, Vol.38 (11), p.2023-2031 |
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| subjects | Biological and medical sciences Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Double-Blind Method Enzyme Inhibitors - blood Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - urine Feces - chemistry Female General pharmacology Humans Janus Kinase 1 - antagonists & inhibitors Janus Kinase 2 - antagonists & inhibitors Male Medical sciences Metabolic Clearance Rate Molecular Structure Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions Pharmacology. Drug treatments Pyrazoles - blood Pyrazoles - metabolism Pyrazoles - pharmacokinetics Pyrazoles - urine Tandem Mass Spectrometry |
| title | Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans |
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