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Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies
Purpose The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. Methods In study A, 40 Japanese and 16 w...
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| Published in: | European journal of clinical pharmacology 2016-01, Vol.72 (1), p.61-71 |
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| container_title | European journal of clinical pharmacology |
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| creator | Martin, Paul Cheung, S. Y. Amy Yen, Mark Han, David Gillen, Michael |
| description | Purpose
The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling.
Methods
In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood.
Results
Mean maximum plasma concentration (
C
max
) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses.
C
max
and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal ( |
| doi_str_mv | 10.1007/s00228-015-1961-5 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1785739561</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3912253671</sourcerecordid><originalsourceid>FETCH-LOGICAL-c438t-cac4496d7279bcc925faa78030302461bb87fedcd26d4b23aad7723fddaaf7a23</originalsourceid><addsrcrecordid>eNp1kc1u1TAQhS1ERS-FB2CDLLFhE_BPEifs0BU_RZW6gXU0sZ3WlyQOHkdVeaW-JBPdFiGkygtb4--cY-sw9kqKd1II8x6FUKophKwK2dayqJ6wnSy1KqQo5VO2E0LLom6NOGXPEQ-CwFboZ-xU1SUdKr1jd_trSGCzT-E35BBnHgeerz13AZeI4WE0RMwwETGHnoeZf4MFZo-e49ofvM1IQzuuLsxXfCHLCWz8GWafg-WA6BEnP-dN6dIt78cYHaeAjB948riOZDCkOPF8Ezc9GZ9zO1KahZFjJmOPL9jJACP6l_f7Gfvx-dP3_dfi4vLL-f7jRWFL3eTCgi3LtnZGmba3tlXVAGAaoWmpspZ935jBO-tU7cpeaQBnjNKDcwCDAaXP2Nuj75Lir9Vj7qaA1o8j_Tiu2EnTVEa3VS0JffMfeohrmul1RFVam7LSGyWPlE0RMfmhW1KYIN12UnRbk92xyY4K6rYmu4o0r--d137y7q_ioToC1BFAupqvfPon-lHXPwPtrZ4</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1753374531</pqid></control><display><type>article</type><title>Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies</title><source>Springer Nature</source><creator>Martin, Paul ; Cheung, S. Y. Amy ; Yen, Mark ; Han, David ; Gillen, Michael</creator><creatorcontrib>Martin, Paul ; Cheung, S. Y. Amy ; Yen, Mark ; Han, David ; Gillen, Michael</creatorcontrib><description>Purpose
The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling.
Methods
In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood.
Results
Mean maximum plasma concentration (
C
max
) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses.
C
max
and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses.
Conclusions
Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-015-1961-5</identifier><identifier>PMID: 26490353</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adult ; Asian Continental Ancestry Group ; Biomedical and Life Sciences ; Biomedicine ; Blood ; Double-Blind Method ; Erythrocytes - metabolism ; Female ; Humans ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Kinetics ; Male ; Oxazines - blood ; Oxazines - pharmacokinetics ; Oxazines - urine ; Pharmacokinetics and Disposition ; Pharmacology ; Pharmacology/Toxicology ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Pyridines - blood ; Pyridines - pharmacokinetics ; Pyridines - urine ; Rheumatoid arthritis ; Studies ; Syk Kinase ; Young Adult</subject><ispartof>European journal of clinical pharmacology, 2016-01, Vol.72 (1), p.61-71</ispartof><rights>Springer-Verlag Berlin Heidelberg 2015</rights><rights>Springer-Verlag Berlin Heidelberg 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-cac4496d7279bcc925faa78030302461bb87fedcd26d4b23aad7723fddaaf7a23</citedby><cites>FETCH-LOGICAL-c438t-cac4496d7279bcc925faa78030302461bb87fedcd26d4b23aad7723fddaaf7a23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26490353$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martin, Paul</creatorcontrib><creatorcontrib>Cheung, S. Y. Amy</creatorcontrib><creatorcontrib>Yen, Mark</creatorcontrib><creatorcontrib>Han, David</creatorcontrib><creatorcontrib>Gillen, Michael</creatorcontrib><title>Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><addtitle>Eur J Clin Pharmacol</addtitle><description>Purpose
The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling.
Methods
In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood.
Results
Mean maximum plasma concentration (
C
max
) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses.
C
max
and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses.
Conclusions
Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.</description><subject>Adult</subject><subject>Asian Continental Ancestry Group</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood</subject><subject>Double-Blind Method</subject><subject>Erythrocytes - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Kinetics</subject><subject>Male</subject><subject>Oxazines - blood</subject><subject>Oxazines - pharmacokinetics</subject><subject>Oxazines - urine</subject><subject>Pharmacokinetics and Disposition</subject><subject>Pharmacology</subject><subject>Pharmacology/Toxicology</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Pyridines - blood</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - urine</subject><subject>Rheumatoid arthritis</subject><subject>Studies</subject><subject>Syk Kinase</subject><subject>Young Adult</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp1kc1u1TAQhS1ERS-FB2CDLLFhE_BPEifs0BU_RZW6gXU0sZ3WlyQOHkdVeaW-JBPdFiGkygtb4--cY-sw9kqKd1II8x6FUKophKwK2dayqJ6wnSy1KqQo5VO2E0LLom6NOGXPEQ-CwFboZ-xU1SUdKr1jd_trSGCzT-E35BBnHgeerz13AZeI4WE0RMwwETGHnoeZf4MFZo-e49ofvM1IQzuuLsxXfCHLCWz8GWafg-WA6BEnP-dN6dIt78cYHaeAjB948riOZDCkOPF8Ezc9GZ9zO1KahZFjJmOPL9jJACP6l_f7Gfvx-dP3_dfi4vLL-f7jRWFL3eTCgi3LtnZGmba3tlXVAGAaoWmpspZ935jBO-tU7cpeaQBnjNKDcwCDAaXP2Nuj75Lir9Vj7qaA1o8j_Tiu2EnTVEa3VS0JffMfeohrmul1RFVam7LSGyWPlE0RMfmhW1KYIN12UnRbk92xyY4K6rYmu4o0r--d137y7q_ioToC1BFAupqvfPon-lHXPwPtrZ4</recordid><startdate>20160101</startdate><enddate>20160101</enddate><creator>Martin, Paul</creator><creator>Cheung, S. Y. Amy</creator><creator>Yen, Mark</creator><creator>Han, David</creator><creator>Gillen, Michael</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><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>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20160101</creationdate><title>Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies</title><author>Martin, Paul ; Cheung, S. Y. Amy ; Yen, Mark ; Han, David ; Gillen, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-cac4496d7279bcc925faa78030302461bb87fedcd26d4b23aad7723fddaaf7a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>Asian Continental Ancestry Group</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blood</topic><topic>Double-Blind Method</topic><topic>Erythrocytes - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Kinetics</topic><topic>Male</topic><topic>Oxazines - blood</topic><topic>Oxazines - pharmacokinetics</topic><topic>Oxazines - urine</topic><topic>Pharmacokinetics and Disposition</topic><topic>Pharmacology</topic><topic>Pharmacology/Toxicology</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Pyridines - blood</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - urine</topic><topic>Rheumatoid arthritis</topic><topic>Studies</topic><topic>Syk Kinase</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martin, Paul</creatorcontrib><creatorcontrib>Cheung, S. Y. Amy</creatorcontrib><creatorcontrib>Yen, Mark</creatorcontrib><creatorcontrib>Han, David</creatorcontrib><creatorcontrib>Gillen, Michael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martin, Paul</au><au>Cheung, S. Y. Amy</au><au>Yen, Mark</au><au>Han, David</au><au>Gillen, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies</atitle><jtitle>European journal of clinical pharmacology</jtitle><stitle>Eur J Clin Pharmacol</stitle><addtitle>Eur J Clin Pharmacol</addtitle><date>2016-01-01</date><risdate>2016</risdate><volume>72</volume><issue>1</issue><spage>61</spage><epage>71</epage><pages>61-71</pages><issn>0031-6970</issn><eissn>1432-1041</eissn><abstract>Purpose
The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling.
Methods
In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood.
Results
Mean maximum plasma concentration (
C
max
) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses.
C
max
and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses.
Conclusions
Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>26490353</pmid><doi>10.1007/s00228-015-1961-5</doi><tpages>11</tpages></addata></record> |
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| issn | 0031-6970 1432-1041 |
| language | eng |
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| source | Springer Nature |
| subjects | Adult Asian Continental Ancestry Group Biomedical and Life Sciences Biomedicine Blood Double-Blind Method Erythrocytes - metabolism Female Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Kinetics Male Oxazines - blood Oxazines - pharmacokinetics Oxazines - urine Pharmacokinetics and Disposition Pharmacology Pharmacology/Toxicology Protein-Tyrosine Kinases - antagonists & inhibitors Pyridines - blood Pyridines - pharmacokinetics Pyridines - urine Rheumatoid arthritis Studies Syk Kinase Young Adult |
| title | Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies |
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