Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound
Purpose The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro in...
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| creator | Mao, Jialin Fan, Peter Wong, Susan Wang, Jianshuang Ismaili, Moulay Hicham Alaoui Dean, Brian Hop, Cornelis E. C. A. Wright, Matthew Chen, Yuan |
| description | Purpose
The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of
in vitro
induction data to
in vivo
findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.
Methods
Pharmacokinetic and induction potency (
in vitro
and
in vivo
) of G2917 in monkeys, and the
in vitro
human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in
in vivo
studies. The static mechanistic model was used to quantitatively understand the
in vitro
-
in vivo
extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).
Results
All
in vitro
and
in vivo
data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.
Conclusions
The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study. |
| doi_str_mv | 10.1007/s11095-017-2246-8 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_journals_1951508864</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A747438826</galeid><sourcerecordid>A747438826</sourcerecordid><originalsourceid>FETCH-LOGICAL-c439t-2c9073b99a4511d139419105bc37bc82f437572e798ced306cb1fa75a9c997e33</originalsourceid><addsrcrecordid>eNp1kV9vFCEUxYnR2LX6AXwxJD5P5QKzgG-bsbZNNrFxNdEnwjDMhDoDK8wY960fXZqt_xINDze5_M69Bw5Cz4GcASHiVQYgqq4IiIpSvq7kA7SCWrBKEf7pIVoRQXklBYcT9CTnG0KIBMUfoxMqJdRM0RW63c3JzG444D4m3Hy-Zht8FbrFzj4G_N7nL3iTs8t5cmHGfYoTvk7Ojj54a0a880MoZY74cplMeI0Nbkx2-Py7mfajw7EvnW1ZUO1mMzj8xmcbv7l0wE2c9nEJ3VP0qDdjds_u6yn6-Pb8Q3NZbd9dXDWbbWU5U3NFrSKCtUoZXgN0wBQHBaRuLROtlbTnTNSCOqGkdR0ja9tCb0RtlFVKOMZO0cvj3H2KXxeXZ30Tl1TMZw2qhppIuea_qcGMTvvQx_I9diqu9UZwwZmUdF2os39Q5XRu8jYG1_vS_0sAR4FNMefker1PfjLpoIHouyj1MUpdotR3UWpZNC_uDS_t5Lpfip_ZFYAegVyuwuDSHy_679QfXoOmpA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1951508864</pqid></control><display><type>article</type><title>Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Mao, Jialin ; Fan, Peter ; Wong, Susan ; Wang, Jianshuang ; Ismaili, Moulay Hicham Alaoui ; Dean, Brian ; Hop, Cornelis E. C. A. ; Wright, Matthew ; Chen, Yuan</creator><creatorcontrib>Mao, Jialin ; Fan, Peter ; Wong, Susan ; Wang, Jianshuang ; Ismaili, Moulay Hicham Alaoui ; Dean, Brian ; Hop, Cornelis E. C. A. ; Wright, Matthew ; Chen, Yuan</creatorcontrib><description>Purpose
The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of
in vitro
induction data to
in vivo
findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.
Methods
Pharmacokinetic and induction potency (
in vitro
and
in vivo
) of G2917 in monkeys, and the
in vitro
human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in
in vivo
studies. The static mechanistic model was used to quantitatively understand the
in vitro
-
in vivo
extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).
Results
All
in vitro
and
in vivo
data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.
Conclusions
The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-017-2246-8</identifier><identifier>PMID: 28815392</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Administration, Oral ; Animals ; Biochemistry ; Bioindicators ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Computer Simulation ; Cortisol ; Cytochrome P-450 CYP3A - biosynthesis ; Drug Discovery ; Drug dosages ; Drug Interactions ; Enzyme Induction ; Exposure ; Extrapolation ; Humans ; Hydrocortisone - analogs & derivatives ; Hydrocortisone - metabolism ; Hydroxycholesterols - metabolism ; Liability ; Liver ; Liver - drug effects ; Liver - metabolism ; Macaca fascicularis ; Medical Law ; Medical research ; Medicine, Experimental ; Midazolam - pharmacology ; Models, Biological ; Monkeys ; Pharmacokinetics ; Pharmacology/Toxicology ; Pharmacy ; Research Paper ; Rifampin - pharmacology ; Risk assessment ; RNA, Messenger - biosynthesis ; Toxicology</subject><ispartof>Pharmaceutical research, 2017-11, Vol.34 (11), p.2403-2414</ispartof><rights>Springer Science+Business Media, LLC 2017</rights><rights>COPYRIGHT 2017 Springer</rights><rights>Pharmaceutical Research is a copyright of Springer, 2017.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-2c9073b99a4511d139419105bc37bc82f437572e798ced306cb1fa75a9c997e33</citedby><cites>FETCH-LOGICAL-c439t-2c9073b99a4511d139419105bc37bc82f437572e798ced306cb1fa75a9c997e33</cites><orcidid>0000-0001-9283-4819</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11095-017-2246-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11095-017-2246-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28815392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mao, Jialin</creatorcontrib><creatorcontrib>Fan, Peter</creatorcontrib><creatorcontrib>Wong, Susan</creatorcontrib><creatorcontrib>Wang, Jianshuang</creatorcontrib><creatorcontrib>Ismaili, Moulay Hicham Alaoui</creatorcontrib><creatorcontrib>Dean, Brian</creatorcontrib><creatorcontrib>Hop, Cornelis E. C. A.</creatorcontrib><creatorcontrib>Wright, Matthew</creatorcontrib><creatorcontrib>Chen, Yuan</creatorcontrib><title>Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>Purpose
The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of
in vitro
induction data to
in vivo
findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.
Methods
Pharmacokinetic and induction potency (
in vitro
and
in vivo
) of G2917 in monkeys, and the
in vitro
human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in
in vivo
studies. The static mechanistic model was used to quantitatively understand the
in vitro
-
in vivo
extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).
Results
All
in vitro
and
in vivo
data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.
Conclusions
The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Bioindicators</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Computer Simulation</subject><subject>Cortisol</subject><subject>Cytochrome P-450 CYP3A - biosynthesis</subject><subject>Drug Discovery</subject><subject>Drug dosages</subject><subject>Drug Interactions</subject><subject>Enzyme Induction</subject><subject>Exposure</subject><subject>Extrapolation</subject><subject>Humans</subject><subject>Hydrocortisone - analogs & derivatives</subject><subject>Hydrocortisone - metabolism</subject><subject>Hydroxycholesterols - metabolism</subject><subject>Liability</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Macaca fascicularis</subject><subject>Medical Law</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Midazolam - pharmacology</subject><subject>Models, Biological</subject><subject>Monkeys</subject><subject>Pharmacokinetics</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Research Paper</subject><subject>Rifampin - pharmacology</subject><subject>Risk assessment</subject><subject>RNA, Messenger - biosynthesis</subject><subject>Toxicology</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kV9vFCEUxYnR2LX6AXwxJD5P5QKzgG-bsbZNNrFxNdEnwjDMhDoDK8wY960fXZqt_xINDze5_M69Bw5Cz4GcASHiVQYgqq4IiIpSvq7kA7SCWrBKEf7pIVoRQXklBYcT9CTnG0KIBMUfoxMqJdRM0RW63c3JzG444D4m3Hy-Zht8FbrFzj4G_N7nL3iTs8t5cmHGfYoTvk7Ojj54a0a880MoZY74cplMeI0Nbkx2-Py7mfajw7EvnW1ZUO1mMzj8xmcbv7l0wE2c9nEJ3VP0qDdjds_u6yn6-Pb8Q3NZbd9dXDWbbWU5U3NFrSKCtUoZXgN0wBQHBaRuLROtlbTnTNSCOqGkdR0ja9tCb0RtlFVKOMZO0cvj3H2KXxeXZ30Tl1TMZw2qhppIuea_qcGMTvvQx_I9diqu9UZwwZmUdF2os39Q5XRu8jYG1_vS_0sAR4FNMefker1PfjLpoIHouyj1MUpdotR3UWpZNC_uDS_t5Lpfip_ZFYAegVyuwuDSHy_679QfXoOmpA</recordid><startdate>20171101</startdate><enddate>20171101</enddate><creator>Mao, Jialin</creator><creator>Fan, Peter</creator><creator>Wong, Susan</creator><creator>Wang, Jianshuang</creator><creator>Ismaili, Moulay Hicham Alaoui</creator><creator>Dean, Brian</creator><creator>Hop, Cornelis E. C. A.</creator><creator>Wright, Matthew</creator><creator>Chen, Yuan</creator><general>Springer US</general><general>Springer</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>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>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><orcidid>https://orcid.org/0000-0001-9283-4819</orcidid></search><sort><creationdate>20171101</creationdate><title>Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound</title><author>Mao, Jialin ; Fan, Peter ; Wong, Susan ; Wang, Jianshuang ; Ismaili, Moulay Hicham Alaoui ; Dean, Brian ; Hop, Cornelis E. C. A. ; Wright, Matthew ; Chen, Yuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-2c9073b99a4511d139419105bc37bc82f437572e798ced306cb1fa75a9c997e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Bioindicators</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Computer Simulation</topic><topic>Cortisol</topic><topic>Cytochrome P-450 CYP3A - biosynthesis</topic><topic>Drug Discovery</topic><topic>Drug dosages</topic><topic>Drug Interactions</topic><topic>Enzyme Induction</topic><topic>Exposure</topic><topic>Extrapolation</topic><topic>Humans</topic><topic>Hydrocortisone - analogs & derivatives</topic><topic>Hydrocortisone - metabolism</topic><topic>Hydroxycholesterols - metabolism</topic><topic>Liability</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Macaca fascicularis</topic><topic>Medical Law</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Midazolam - pharmacology</topic><topic>Models, Biological</topic><topic>Monkeys</topic><topic>Pharmacokinetics</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Research Paper</topic><topic>Rifampin - pharmacology</topic><topic>Risk assessment</topic><topic>RNA, Messenger - biosynthesis</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mao, Jialin</creatorcontrib><creatorcontrib>Fan, Peter</creatorcontrib><creatorcontrib>Wong, Susan</creatorcontrib><creatorcontrib>Wang, Jianshuang</creatorcontrib><creatorcontrib>Ismaili, Moulay Hicham Alaoui</creatorcontrib><creatorcontrib>Dean, Brian</creatorcontrib><creatorcontrib>Hop, Cornelis E. C. A.</creatorcontrib><creatorcontrib>Wright, Matthew</creatorcontrib><creatorcontrib>Chen, Yuan</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>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 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>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><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mao, Jialin</au><au>Fan, Peter</au><au>Wong, Susan</au><au>Wang, Jianshuang</au><au>Ismaili, Moulay Hicham Alaoui</au><au>Dean, Brian</au><au>Hop, Cornelis E. C. A.</au><au>Wright, Matthew</au><au>Chen, Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2017-11-01</date><risdate>2017</risdate><volume>34</volume><issue>11</issue><spage>2403</spage><epage>2414</epage><pages>2403-2414</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><abstract>Purpose
The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of
in vitro
induction data to
in vivo
findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.
Methods
Pharmacokinetic and induction potency (
in vitro
and
in vivo
) of G2917 in monkeys, and the
in vitro
human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in
in vivo
studies. The static mechanistic model was used to quantitatively understand the
in vitro
-
in vivo
extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).
Results
All
in vitro
and
in vivo
data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.
Conclusions
The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>28815392</pmid><doi>10.1007/s11095-017-2246-8</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-9283-4819</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0724-8741 |
| ispartof | Pharmaceutical research, 2017-11, Vol.34 (11), p.2403-2414 |
| issn | 0724-8741 1573-904X |
| language | eng |
| recordid | cdi_proquest_journals_1951508864 |
| source | MEDLINE; SpringerLink Journals |
| subjects | Administration, Oral Animals Biochemistry Bioindicators Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Computer Simulation Cortisol Cytochrome P-450 CYP3A - biosynthesis Drug Discovery Drug dosages Drug Interactions Enzyme Induction Exposure Extrapolation Humans Hydrocortisone - analogs & derivatives Hydrocortisone - metabolism Hydroxycholesterols - metabolism Liability Liver Liver - drug effects Liver - metabolism Macaca fascicularis Medical Law Medical research Medicine, Experimental Midazolam - pharmacology Models, Biological Monkeys Pharmacokinetics Pharmacology/Toxicology Pharmacy Research Paper Rifampin - pharmacology Risk assessment RNA, Messenger - biosynthesis Toxicology |
| title | Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound |
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