A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High‐Dose Methotrexate: Data From the OS2006/Sarcoma‐09 Trial
Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK‐pharmacogenetic model to evaluate the pa...
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| Veröffentlicht in: | Journal of clinical pharmacology 2018-12, Vol.58 (12), p.1541-1549 |
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| creator | Lui, Gabrielle Treluyer, Jean‐Marc Fresneau, Brice Piperno‐Neumann, Sophie Gaspar, Nathalie Corradini, Nadège Gentet, Jean‐Claude Marec Berard, Perrine Laurence, Valérie Schneider, Pascale Entz‐Werle, Natacha Pacquement, Hélène Millot, Frédéric Taque, Sophie Freycon, Claire Lervat, Cyril Deley, Marie Cécile Mahier Ait Oukhatar, Céline Brugieres, Laurence Teuff, Gwénaël Bouazza, Naïm |
| description | Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK‐pharmacogenetic model to evaluate the part of between‐subject variability due to single‐nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma‐09 trial (a multicenter, open‐label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed‐effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK‐pharmacogenetic analysis. A 2‐compartment model adequately described the data. Although high‐dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between‐subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers. |
| doi_str_mv | 10.1002/jcph.1252 |
| format | Article |
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This prospective study aimed to develop a population PK‐pharmacogenetic model to evaluate the part of between‐subject variability due to single‐nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma‐09 trial (a multicenter, open‐label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed‐effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK‐pharmacogenetic analysis. A 2‐compartment model adequately described the data. Although high‐dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between‐subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.1252</identifier><identifier>PMID: 29791011</identifier><language>eng</language><publisher>England: American College of Clinical Pharmacology</publisher><subject>ABCG2 gene ; Body weight ; Bone cancer ; Data processing ; Gene polymorphism ; Immunology ; Immunomodulators ; Life Sciences ; Likelihood ratio ; Methotrexate ; Osteosarcoma ; pharmacogenetics ; Pharmacokinetics ; population pharmacokinetics ; Sarcoma ; Single-nucleotide polymorphism ; Surface area ; Variability</subject><ispartof>Journal of clinical pharmacology, 2018-12, Vol.58 (12), p.1541-1549</ispartof><rights>2018, The American College of Clinical Pharmacology</rights><rights>2018 American College of Clinical Pharmacology</rights><rights>2018, The American College of Clinical Pharmacology.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4252-d301e773cb059a8ed5333d944f1ae80f66574f3cc546f834748aa5cbc1c3df663</citedby><cites>FETCH-LOGICAL-c4252-d301e773cb059a8ed5333d944f1ae80f66574f3cc546f834748aa5cbc1c3df663</cites><orcidid>0000-0002-2946-4592 ; 0000-0001-9915-2810 ; 0000-0001-7603-7828</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcph.1252$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcph.1252$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29791011$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02413928$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Lui, Gabrielle</creatorcontrib><creatorcontrib>Treluyer, Jean‐Marc</creatorcontrib><creatorcontrib>Fresneau, Brice</creatorcontrib><creatorcontrib>Piperno‐Neumann, Sophie</creatorcontrib><creatorcontrib>Gaspar, Nathalie</creatorcontrib><creatorcontrib>Corradini, Nadège</creatorcontrib><creatorcontrib>Gentet, Jean‐Claude</creatorcontrib><creatorcontrib>Marec Berard, Perrine</creatorcontrib><creatorcontrib>Laurence, Valérie</creatorcontrib><creatorcontrib>Schneider, Pascale</creatorcontrib><creatorcontrib>Entz‐Werle, Natacha</creatorcontrib><creatorcontrib>Pacquement, Hélène</creatorcontrib><creatorcontrib>Millot, Frédéric</creatorcontrib><creatorcontrib>Taque, Sophie</creatorcontrib><creatorcontrib>Freycon, Claire</creatorcontrib><creatorcontrib>Lervat, Cyril</creatorcontrib><creatorcontrib>Deley, Marie Cécile</creatorcontrib><creatorcontrib>Mahier Ait Oukhatar, Céline</creatorcontrib><creatorcontrib>Brugieres, Laurence</creatorcontrib><creatorcontrib>Teuff, Gwénaël</creatorcontrib><creatorcontrib>Bouazza, Naïm</creatorcontrib><creatorcontrib>Sarcoma Group of UNICANCER</creatorcontrib><creatorcontrib>for the Sarcoma Group of UNICANCER</creatorcontrib><title>A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High‐Dose Methotrexate: Data From the OS2006/Sarcoma‐09 Trial</title><title>Journal of clinical pharmacology</title><addtitle>J Clin Pharmacol</addtitle><description>Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK‐pharmacogenetic model to evaluate the part of between‐subject variability due to single‐nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma‐09 trial (a multicenter, open‐label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed‐effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK‐pharmacogenetic analysis. A 2‐compartment model adequately described the data. Although high‐dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between‐subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.</description><subject>ABCG2 gene</subject><subject>Body weight</subject><subject>Bone cancer</subject><subject>Data processing</subject><subject>Gene polymorphism</subject><subject>Immunology</subject><subject>Immunomodulators</subject><subject>Life Sciences</subject><subject>Likelihood ratio</subject><subject>Methotrexate</subject><subject>Osteosarcoma</subject><subject>pharmacogenetics</subject><subject>Pharmacokinetics</subject><subject>population pharmacokinetics</subject><subject>Sarcoma</subject><subject>Single-nucleotide polymorphism</subject><subject>Surface area</subject><subject>Variability</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kc9uEzEQxlcIRNPCgRdAlrjQwzb-t_-4RSkloKBEahFHa-Kd7TrdjYPtUHLjETjxgDwJDglBQnAa6ZvffGPPlyTPGL1glPLhUq_bC8Yz_iAZsCzjqcypfJgMKK1YygtKT5JT75eUslxm7HFywquiYpSxQfJ9ROYtuB60vTMrDEYTWNVH7Rb32mgF3dYbT2xDZj6g9eC07YHMIRhcBU9uHELAmnw0oSUTc9v--Prt0nok7zG0Njj8EtuvyCUEIFfO9iS0SGbXnNJ8eL03ixO0ikYGuifJowY6j08P9Sz5cPX6ZjxJp7M3b8ejaapl_G5aC8qwKIRe0KyCEutMCFFXUjYMsKRNnmeFbITWmcybUshClgCZXmimRR274iw53_u20Km1Mz24rbJg1GQ0VTuNcslExcvPLLIv9-za2U8b9EH1xmvsOlih3XjFqRSskFVeRfTFX-jSbly8YaSYoJyXmeB_lmtnvXfYHF_AqNoFq3bBql2wkX1-cNwseqyP5O8kI5DugXvbBXT-rtvco1MtQhfafxoOD7zpcPv_zerdeD75NfETcWK88g</recordid><startdate>201812</startdate><enddate>201812</enddate><creator>Lui, Gabrielle</creator><creator>Treluyer, Jean‐Marc</creator><creator>Fresneau, Brice</creator><creator>Piperno‐Neumann, Sophie</creator><creator>Gaspar, Nathalie</creator><creator>Corradini, Nadège</creator><creator>Gentet, Jean‐Claude</creator><creator>Marec Berard, Perrine</creator><creator>Laurence, Valérie</creator><creator>Schneider, Pascale</creator><creator>Entz‐Werle, Natacha</creator><creator>Pacquement, Hélène</creator><creator>Millot, Frédéric</creator><creator>Taque, Sophie</creator><creator>Freycon, Claire</creator><creator>Lervat, Cyril</creator><creator>Deley, Marie Cécile</creator><creator>Mahier Ait Oukhatar, Céline</creator><creator>Brugieres, Laurence</creator><creator>Teuff, Gwénaël</creator><creator>Bouazza, Naïm</creator><general>American College of Clinical Pharmacology</general><general>Wiley Subscription Services, Inc</general><general>Wiley</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2946-4592</orcidid><orcidid>https://orcid.org/0000-0001-9915-2810</orcidid><orcidid>https://orcid.org/0000-0001-7603-7828</orcidid></search><sort><creationdate>201812</creationdate><title>A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High‐Dose Methotrexate: Data From the OS2006/Sarcoma‐09 Trial</title><author>Lui, Gabrielle ; 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| ispartof | Journal of clinical pharmacology, 2018-12, Vol.58 (12), p.1541-1549 |
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| source | Wiley Online Library Journals Frontfile Complete |
| subjects | ABCG2 gene Body weight Bone cancer Data processing Gene polymorphism Immunology Immunomodulators Life Sciences Likelihood ratio Methotrexate Osteosarcoma pharmacogenetics Pharmacokinetics population pharmacokinetics Sarcoma Single-nucleotide polymorphism Surface area Variability |
| title | A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High‐Dose Methotrexate: Data From the OS2006/Sarcoma‐09 Trial |
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