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Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model
Purpose Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. Method...
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| Published in: | European journal of clinical pharmacology 2018-08, Vol.74 (8), p.1029-1036 |
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| Main Authors: | , , , , , , , , , |
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| container_end_page | 1036 |
| container_issue | 8 |
| container_start_page | 1029 |
| container_title | European journal of clinical pharmacology |
| container_volume | 74 |
| creator | Mei, Shenghui Feng, Weixing Zhu, Leting Li, Xingang Yu, Yazhen Yang, Weili Gao, Baoqin Wu, Xiaojuan Fang, Fang Zhao, Zhigang |
| description | Purpose
Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy.
Methods
A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated.
Results
In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)
0.59
× e
UGT-CYP
for TDD included model and 0.70 × (BSA/0.99)
0.57
× e
UGT-CYP
for BSA included model. The precision of all parameters were acceptable (relative standard error |
| doi_str_mv | 10.1007/s00228-018-2440-6 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2027069679</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2027069679</sourcerecordid><originalsourceid>FETCH-LOGICAL-c372t-3b974d1b1bb80057ded430ba014ea3cb1acf6c67ee38f64684ed719ee11b21443</originalsourceid><addsrcrecordid>eNp1kcFu1DAQhi1URLeFB-CCLPXCoYEZ22sn3NpVKUiV4NAeOEWOM-m6JHGwE1AvPHu92hYkJE4eyd__j62PsdcI7xDAvE8AQpQFYFkIpaDQz9gKlRQFgsIDtgKQWOjKwCE7SukOANcVyBfsUFRa6wrEiv2-6DpyMw8d33z7KjZYnfKby2s8K0-5HdvdLM4NDyP_afspBu-4db7lricb7eiI-5G7re_bSCP_5ectp8n3NKX7D9zyKUxLb2ef89PWxsG68N2PNOeaIbTUv2TPO9snevV4HrObjxfXm0_F1ZfLz5uzq8JJI-ZCNpVRLTbYNCXA2rTUKgmNBVRkpWvQuk47bYhk2WmlS0WtwYoIsRGolDxmb_e9-Qs_FkpzPfjkqO_tSGFJtQBhQFfaVBk9-Qe9C0sc8-t2lMZyLbXMFO4pF0NKkbp6in6w8b5GqHdy6r2cOsupd3JqnTNvHpuXZqD2T-LJRgbEHkj5aryl-Hf1_1sfAClhl5o</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2026185363</pqid></control><display><type>article</type><title>Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model</title><source>Springer Link</source><creator>Mei, Shenghui ; Feng, Weixing ; Zhu, Leting ; Li, Xingang ; Yu, Yazhen ; Yang, Weili ; Gao, Baoqin ; Wu, Xiaojuan ; Fang, Fang ; Zhao, Zhigang</creator><creatorcontrib>Mei, Shenghui ; Feng, Weixing ; Zhu, Leting ; Li, Xingang ; Yu, Yazhen ; Yang, Weili ; Gao, Baoqin ; Wu, Xiaojuan ; Fang, Fang ; Zhao, Zhigang</creatorcontrib><description>Purpose
Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy.
Methods
A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated.
Results
In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)
0.59
× e
UGT-CYP
for TDD included model and 0.70 × (BSA/0.99)
0.57
× e
UGT-CYP
for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability.
Conclusion
TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-018-2440-6</identifier><identifier>PMID: 29666902</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Biomedical and Life Sciences ; Biomedicine ; Children ; Epilepsy ; Genetic diversity ; Genetic variance ; Genotypes ; Metabolism ; Pharmacokinetics ; Pharmacokinetics and Disposition ; Pharmacology/Toxicology ; Seizures ; Single-nucleotide polymorphism ; Standard error ; Valproic acid</subject><ispartof>European journal of clinical pharmacology, 2018-08, Vol.74 (8), p.1029-1036</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2018</rights><rights>European Journal of Clinical Pharmacology is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-3b974d1b1bb80057ded430ba014ea3cb1acf6c67ee38f64684ed719ee11b21443</citedby><cites>FETCH-LOGICAL-c372t-3b974d1b1bb80057ded430ba014ea3cb1acf6c67ee38f64684ed719ee11b21443</cites><orcidid>0000-0003-0281-2259</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29666902$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mei, Shenghui</creatorcontrib><creatorcontrib>Feng, Weixing</creatorcontrib><creatorcontrib>Zhu, Leting</creatorcontrib><creatorcontrib>Li, Xingang</creatorcontrib><creatorcontrib>Yu, Yazhen</creatorcontrib><creatorcontrib>Yang, Weili</creatorcontrib><creatorcontrib>Gao, Baoqin</creatorcontrib><creatorcontrib>Wu, Xiaojuan</creatorcontrib><creatorcontrib>Fang, Fang</creatorcontrib><creatorcontrib>Zhao, Zhigang</creatorcontrib><title>Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><addtitle>Eur J Clin Pharmacol</addtitle><description>Purpose
Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy.
Methods
A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated.
Results
In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)
0.59
× e
UGT-CYP
for TDD included model and 0.70 × (BSA/0.99)
0.57
× e
UGT-CYP
for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability.
Conclusion
TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.</description><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Children</subject><subject>Epilepsy</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Genotypes</subject><subject>Metabolism</subject><subject>Pharmacokinetics</subject><subject>Pharmacokinetics and Disposition</subject><subject>Pharmacology/Toxicology</subject><subject>Seizures</subject><subject>Single-nucleotide polymorphism</subject><subject>Standard error</subject><subject>Valproic acid</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kcFu1DAQhi1URLeFB-CCLPXCoYEZ22sn3NpVKUiV4NAeOEWOM-m6JHGwE1AvPHu92hYkJE4eyd__j62PsdcI7xDAvE8AQpQFYFkIpaDQz9gKlRQFgsIDtgKQWOjKwCE7SukOANcVyBfsUFRa6wrEiv2-6DpyMw8d33z7KjZYnfKby2s8K0-5HdvdLM4NDyP_afspBu-4db7lricb7eiI-5G7re_bSCP_5ectp8n3NKX7D9zyKUxLb2ef89PWxsG68N2PNOeaIbTUv2TPO9snevV4HrObjxfXm0_F1ZfLz5uzq8JJI-ZCNpVRLTbYNCXA2rTUKgmNBVRkpWvQuk47bYhk2WmlS0WtwYoIsRGolDxmb_e9-Qs_FkpzPfjkqO_tSGFJtQBhQFfaVBk9-Qe9C0sc8-t2lMZyLbXMFO4pF0NKkbp6in6w8b5GqHdy6r2cOsupd3JqnTNvHpuXZqD2T-LJRgbEHkj5aryl-Hf1_1sfAClhl5o</recordid><startdate>20180801</startdate><enddate>20180801</enddate><creator>Mei, Shenghui</creator><creator>Feng, Weixing</creator><creator>Zhu, Leting</creator><creator>Li, Xingang</creator><creator>Yu, Yazhen</creator><creator>Yang, Weili</creator><creator>Gao, Baoqin</creator><creator>Wu, Xiaojuan</creator><creator>Fang, Fang</creator><creator>Zhao, Zhigang</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><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><orcidid>https://orcid.org/0000-0003-0281-2259</orcidid></search><sort><creationdate>20180801</creationdate><title>Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model</title><author>Mei, Shenghui ; Feng, Weixing ; Zhu, Leting ; Li, Xingang ; Yu, Yazhen ; Yang, Weili ; Gao, Baoqin ; Wu, Xiaojuan ; Fang, Fang ; Zhao, Zhigang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-3b974d1b1bb80057ded430ba014ea3cb1acf6c67ee38f64684ed719ee11b21443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Children</topic><topic>Epilepsy</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Genotypes</topic><topic>Metabolism</topic><topic>Pharmacokinetics</topic><topic>Pharmacokinetics and Disposition</topic><topic>Pharmacology/Toxicology</topic><topic>Seizures</topic><topic>Single-nucleotide polymorphism</topic><topic>Standard error</topic><topic>Valproic acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mei, Shenghui</creatorcontrib><creatorcontrib>Feng, Weixing</creatorcontrib><creatorcontrib>Zhu, Leting</creatorcontrib><creatorcontrib>Li, Xingang</creatorcontrib><creatorcontrib>Yu, Yazhen</creatorcontrib><creatorcontrib>Yang, Weili</creatorcontrib><creatorcontrib>Gao, Baoqin</creatorcontrib><creatorcontrib>Wu, Xiaojuan</creatorcontrib><creatorcontrib>Fang, Fang</creatorcontrib><creatorcontrib>Zhao, Zhigang</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest 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>Mei, Shenghui</au><au>Feng, Weixing</au><au>Zhu, Leting</au><au>Li, Xingang</au><au>Yu, Yazhen</au><au>Yang, Weili</au><au>Gao, Baoqin</au><au>Wu, Xiaojuan</au><au>Fang, Fang</au><au>Zhao, Zhigang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model</atitle><jtitle>European journal of clinical pharmacology</jtitle><stitle>Eur J Clin Pharmacol</stitle><addtitle>Eur J Clin Pharmacol</addtitle><date>2018-08-01</date><risdate>2018</risdate><volume>74</volume><issue>8</issue><spage>1029</spage><epage>1036</epage><pages>1029-1036</pages><issn>0031-6970</issn><eissn>1432-1041</eissn><abstract>Purpose
Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy.
Methods
A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated.
Results
In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)
0.59
× e
UGT-CYP
for TDD included model and 0.70 × (BSA/0.99)
0.57
× e
UGT-CYP
for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability.
Conclusion
TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>29666902</pmid><doi>10.1007/s00228-018-2440-6</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-0281-2259</orcidid></addata></record> |
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| language | eng |
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| subjects | Biomedical and Life Sciences Biomedicine Children Epilepsy Genetic diversity Genetic variance Genotypes Metabolism Pharmacokinetics Pharmacokinetics and Disposition Pharmacology/Toxicology Seizures Single-nucleotide polymorphism Standard error Valproic acid |
| title | Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model |
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