Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia
Purpose Barasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK),...
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creator | Dennis, Mike Davies, Michelle Oliver, Stuart D’Souza, Roy Pike, Laura Stockman, Paul |
description | Purpose
Barasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK), metabolic and excretion profiles of barasertib and barasertib-hQPA were characterized in this open-label Phase I study.
Methods
Five patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [
14
C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.
Results
Barasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72–82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.
Conclusions
The PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes. |
doi_str_mv | 10.1007/s00280-012-1939-2 |
format | Article |
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Barasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK), metabolic and excretion profiles of barasertib and barasertib-hQPA were characterized in this open-label Phase I study.
Methods
Five patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [
14
C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.
Results
Barasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72–82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.
Conclusions
The PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-012-1939-2</identifier><identifier>PMID: 22864876</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adult ; Aged ; Antineoplastic agents ; Aurora Kinase B ; Aurora Kinases ; Biological and medical sciences ; Cancer Research ; Female ; Hematologic and hematopoietic diseases ; Humans ; Infusions, Intravenous ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - pathology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Middle Aged ; Oncology ; Organophosphates - adverse effects ; Organophosphates - pharmacokinetics ; Organophosphates - therapeutic use ; Original ; Original Article ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Prodrugs ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Quinazolines - adverse effects ; Quinazolines - pharmacokinetics ; Quinazolines - therapeutic use ; Remission Induction ; Time Factors ; Treatment Outcome</subject><ispartof>Cancer chemotherapy and pharmacology, 2012-09, Vol.70 (3), p.461-469</ispartof><rights>The Author(s) 2012</rights><rights>2015 INIST-CNRS</rights><rights>Springer-Verlag 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c533t-5258917ad36bad4e0204cf3bd4d6138ebb5152ebecce188700fe8fe11d0b07f13</citedby><cites>FETCH-LOGICAL-c533t-5258917ad36bad4e0204cf3bd4d6138ebb5152ebecce188700fe8fe11d0b07f13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00280-012-1939-2$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00280-012-1939-2$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26286617$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22864876$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dennis, Mike</creatorcontrib><creatorcontrib>Davies, Michelle</creatorcontrib><creatorcontrib>Oliver, Stuart</creatorcontrib><creatorcontrib>D’Souza, Roy</creatorcontrib><creatorcontrib>Pike, Laura</creatorcontrib><creatorcontrib>Stockman, Paul</creatorcontrib><title>Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
Barasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK), metabolic and excretion profiles of barasertib and barasertib-hQPA were characterized in this open-label Phase I study.
Methods
Five patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [
14
C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.
Results
Barasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72–82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.
Conclusions
The PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Aurora Kinase B</subject><subject>Aurora Kinases</subject><subject>Biological and medical sciences</subject><subject>Cancer Research</subject><subject>Female</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Organophosphates - adverse effects</subject><subject>Organophosphates - pharmacokinetics</subject><subject>Organophosphates - therapeutic use</subject><subject>Original</subject><subject>Original Article</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Prodrugs</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Quinazolines - adverse effects</subject><subject>Quinazolines - pharmacokinetics</subject><subject>Quinazolines - therapeutic use</subject><subject>Remission Induction</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1ks1u1TAQhSMEoqXwAGyQJYRUJALjnyTOBulS_ipVggVs2Fi2M2ncJvGt7QD3fXhQfLmXUpBYWfL5zswZzRTFQwrPKUDzIgIwCSVQVtKWtyW7VRxSwVkJUvDbxSFwIcqqAXFQ3IvxAgAE5fxuccCYrIVs6sPix8dBRySnJKal2xDfkzQgWS3BB01ekUs3b2U3D8645AMxOuSPkJwhx6svrymt2FOSPNExYoy_zOtBh0lbn72YnI3PyIRJGz-6OBE9dwS_25AVP-e6ZK2TwzlF8s2lgWi7JCTTBkfvOjLicomT0_eLO70eIz7Yv0fF57dvPp28L88-vDs9WZ2VtuI8lRWrZEsb3fHa6E4gMBC256YTXU25RGOqHBcNWotUygagR9kjpR0YaHrKj4qXu7rrxUzY2Zwr6FGtg5t02Civnfpbmd2gzv1XxQWTFeO5wPG-QPBXC8akJhctjqOe0S9RUckbTlsJbUYf_4Ne-CXMeTxFgTd5r61oMkV3lA0-xoD9dRgKansDancDKt-A2t6AYtnz6OYU147fS8_Akz2go9VjH_RsXfzD1Rms6bY523ExS_M5hpsR_9f9J_tUy9I</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Dennis, Mike</creator><creator>Davies, Michelle</creator><creator>Oliver, Stuart</creator><creator>D’Souza, Roy</creator><creator>Pike, Laura</creator><creator>Stockman, Paul</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</scope><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><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</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>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>20120901</creationdate><title>Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia</title><author>Dennis, Mike ; Davies, Michelle ; Oliver, Stuart ; D’Souza, Roy ; Pike, Laura ; Stockman, Paul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c533t-5258917ad36bad4e0204cf3bd4d6138ebb5152ebecce188700fe8fe11d0b07f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Aurora Kinase B</topic><topic>Aurora Kinases</topic><topic>Biological and medical sciences</topic><topic>Cancer Research</topic><topic>Female</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Infusions, Intravenous</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Oncology</topic><topic>Organophosphates - adverse effects</topic><topic>Organophosphates - pharmacokinetics</topic><topic>Organophosphates - therapeutic use</topic><topic>Original</topic><topic>Original Article</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Prodrugs</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Quinazolines - adverse effects</topic><topic>Quinazolines - pharmacokinetics</topic><topic>Quinazolines - therapeutic use</topic><topic>Remission Induction</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dennis, Mike</creatorcontrib><creatorcontrib>Davies, Michelle</creatorcontrib><creatorcontrib>Oliver, Stuart</creatorcontrib><creatorcontrib>D’Souza, Roy</creatorcontrib><creatorcontrib>Pike, Laura</creatorcontrib><creatorcontrib>Stockman, Paul</creatorcontrib><collection>Springer Nature OA Free Journals</collection><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><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors 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>Public Health Database</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 Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>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>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dennis, Mike</au><au>Davies, Michelle</au><au>Oliver, Stuart</au><au>D’Souza, Roy</au><au>Pike, Laura</au><au>Stockman, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>70</volume><issue>3</issue><spage>461</spage><epage>469</epage><pages>461-469</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Purpose
Barasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK), metabolic and excretion profiles of barasertib and barasertib-hQPA were characterized in this open-label Phase I study.
Methods
Five patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [
14
C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.
Results
Barasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72–82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.
Conclusions
The PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>22864876</pmid><doi>10.1007/s00280-012-1939-2</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Aged Antineoplastic agents Aurora Kinase B Aurora Kinases Biological and medical sciences Cancer Research Female Hematologic and hematopoietic diseases Humans Infusions, Intravenous Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - pathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Medicine Medicine & Public Health Middle Aged Oncology Organophosphates - adverse effects Organophosphates - pharmacokinetics Organophosphates - therapeutic use Original Original Article Pharmacology. Drug treatments Pharmacology/Toxicology Prodrugs Protein-Serine-Threonine Kinases - antagonists & inhibitors Quinazolines - adverse effects Quinazolines - pharmacokinetics Quinazolines - therapeutic use Remission Induction Time Factors Treatment Outcome |
title | Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia |
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