Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population
Background Numerous studies have described the impact of cytochrome P450 3A5 ( CYP3A5 ) genotype on Tacrolimus (TAC) exposure. The purpose of this study was to conduct a comprehensive analysis of genetic and non-genetic factors affecting the TAC dose–exposure relationship over the first year post pe...
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| Veröffentlicht in: | Pediatric nephrology (Berlin, West) West), 2014-10, Vol.29 (10), p.2039-2049 |
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| creator | Lalan, Shwetal Abdel-Rahman, Susan Gaedigk, Andrea Leeder, J. Steven Warady, Bradley A. Dai, Hongying Blowey, Douglas |
| description | Background
Numerous studies have described the impact of cytochrome P450 3A5 (
CYP3A5
) genotype on Tacrolimus (TAC) exposure. The purpose of this study was to conduct a comprehensive analysis of genetic and non-genetic factors affecting the TAC dose–exposure relationship over the first year post pediatric renal transplant.
Methods
Data were collected retrospectively for the first year post-transplant in pediatric renal transplant patients receiving TAC maintenance immunosuppression. The effect of
CYP3A5
genotype (
CYP3A5*3
and
*6
alleles), age, azoles, and corticosteroids on TAC trough concentration normalized for dose (TAC Co/D ng/ml/mg/kg/day) was assessed using a linear mixed model.
Results
Over time, TAC Co/D was lower in recipients with
CYP3A5*1/*3
genotype compared to those with
CYP3A5*3/*3
genotype (44.5 ± 14.4 vs. 107.6 ± 6.4,
p
= 0.03), increased in patients >12 years of age compared to |
| doi_str_mv | 10.1007/s00467-014-2827-2 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_1563061677</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A384439708</galeid><sourcerecordid>A384439708</sourcerecordid><originalsourceid>FETCH-LOGICAL-c541t-215e17c965c0d0b69e036dd248b522851c056392f58107149d4f6612cdaf81e03</originalsourceid><addsrcrecordid>eNp1kl9rFDEUxYModq1-AF8kIBQfOjXJTDIzj8tS_0BBHxTqU8hmbnZTMsmYZB7qpzfjVm1lJQ-B3N-53HtyEHpJyQUlpH2bCGlEWxHaVKxjbcUeoRVtalbRvrt-jFakr2lFGnp9gp6ldEMI6XgnnqIT1nQtZy1bof2lMaAzDgZvvn2u1xzvwId8O8E5ThlisEM6x8oPWP0IDhIOHmelY3B2nBO2His8wWBVjlbjCF45nKPyaXLKZzyFaXYq2-CfoydGuQQv7u5T9PXd5ZfNh-rq0_uPm_VVpXlDc8UoB9rqXnBNBrIVPZBaDEMZeMsZ6zjVhIu6Z4Z3lLS06YfGCEGZHpTpaIFP0ZtD3ymG7zOkLEebNLgyDoQ5SVrkRFDRtgV9_Q96E-ZYNvhFsVrwnrG_1E45kNabUPbTS1O5rrumqfuWdIWqjlDFS4jKBQ_GlucH_MURvpwBRquPCs7uCfagXN6n4ObF2_QQpAewfFJKEYycoh1VvJWUyCU28hAbWWIjl9jIZcdXd07M2xGGP4rfOSkAOwCplPwO4j2r_tv1JzHQyJg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1562365922</pqid></control><display><type>article</type><title>Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population</title><source>MEDLINE</source><source>SpringerNature Journals</source><creator>Lalan, Shwetal ; Abdel-Rahman, Susan ; Gaedigk, Andrea ; Leeder, J. Steven ; Warady, Bradley A. ; Dai, Hongying ; Blowey, Douglas</creator><creatorcontrib>Lalan, Shwetal ; Abdel-Rahman, Susan ; Gaedigk, Andrea ; Leeder, J. Steven ; Warady, Bradley A. ; Dai, Hongying ; Blowey, Douglas</creatorcontrib><description>Background
Numerous studies have described the impact of cytochrome P450 3A5 (
CYP3A5
) genotype on Tacrolimus (TAC) exposure. The purpose of this study was to conduct a comprehensive analysis of genetic and non-genetic factors affecting the TAC dose–exposure relationship over the first year post pediatric renal transplant.
Methods
Data were collected retrospectively for the first year post-transplant in pediatric renal transplant patients receiving TAC maintenance immunosuppression. The effect of
CYP3A5
genotype (
CYP3A5*3
and
*6
alleles), age, azoles, and corticosteroids on TAC trough concentration normalized for dose (TAC Co/D ng/ml/mg/kg/day) was assessed using a linear mixed model.
Results
Over time, TAC Co/D was lower in recipients with
CYP3A5*1/*3
genotype compared to those with
CYP3A5*3/*3
genotype (44.5 ± 14.4 vs. 107.6 ± 6.4,
p
= 0.03), increased in patients >12 years of age compared to < 12 years (93.9 ± 8.7 vs. 53.1 ± 12.9,
p
= 0.007), and decreased by concomitant corticosteroids (69.5 ± 12.7 vs. 89.9 ± 20.0,
p
= 0.04). The observed increased TAC Co/D in the presence of azoles (271 ± 41 vs. 111 ± 91,
p
= 0.016) could be attributed to clotrimazole.
Conclusions
Multiple factors, including
CYP3A5
genotype, and age, influence TAC Co/D in pediatric kidney transplant recipients. Clotrimazole administered as troches also contribute to TAC Co/D variability.</description><identifier>ISSN: 0931-041X</identifier><identifier>EISSN: 1432-198X</identifier><identifier>DOI: 10.1007/s00467-014-2827-2</identifier><identifier>PMID: 24875272</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adolescent ; Adrenal Cortex Hormones - therapeutic use ; Age ; Age Factors ; Anti-Infective Agents, Local - therapeutic use ; Child ; Child, Preschool ; Clotrimazole - therapeutic use ; Cytochrome ; Cytochrome P-450 CYP3A - genetics ; Dosage and administration ; Drug dosages ; Drug therapy ; Enzymes ; Female ; Genotype ; Genotype & phenotype ; Humans ; Immunosuppressive Agents - blood ; Immunosuppressive Agents - therapeutic use ; Infant ; Influence ; Kidney failure ; Kidney Transplantation ; Kidney transplants ; Kidneys ; Male ; Medicine ; Medicine & Public Health ; Metabolism ; Nephrology ; Original Article ; Patients ; Pediatrics ; Polymorphism, Single Nucleotide ; Retrospective Studies ; Steroids ; Tacrolimus ; Tacrolimus - blood ; Tacrolimus - therapeutic use ; Toxicity ; Transplantation ; Urology ; Young Adult</subject><ispartof>Pediatric nephrology (Berlin, West), 2014-10, Vol.29 (10), p.2039-2049</ispartof><rights>IPNA 2014</rights><rights>COPYRIGHT 2014 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-215e17c965c0d0b69e036dd248b522851c056392f58107149d4f6612cdaf81e03</citedby><cites>FETCH-LOGICAL-c541t-215e17c965c0d0b69e036dd248b522851c056392f58107149d4f6612cdaf81e03</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/s00467-014-2827-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00467-014-2827-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27933,27934,41497,42566,51328</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24875272$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lalan, Shwetal</creatorcontrib><creatorcontrib>Abdel-Rahman, Susan</creatorcontrib><creatorcontrib>Gaedigk, Andrea</creatorcontrib><creatorcontrib>Leeder, J. Steven</creatorcontrib><creatorcontrib>Warady, Bradley A.</creatorcontrib><creatorcontrib>Dai, Hongying</creatorcontrib><creatorcontrib>Blowey, Douglas</creatorcontrib><title>Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population</title><title>Pediatric nephrology (Berlin, West)</title><addtitle>Pediatr Nephrol</addtitle><addtitle>Pediatr Nephrol</addtitle><description>Background
Numerous studies have described the impact of cytochrome P450 3A5 (
CYP3A5
) genotype on Tacrolimus (TAC) exposure. The purpose of this study was to conduct a comprehensive analysis of genetic and non-genetic factors affecting the TAC dose–exposure relationship over the first year post pediatric renal transplant.
Methods
Data were collected retrospectively for the first year post-transplant in pediatric renal transplant patients receiving TAC maintenance immunosuppression. The effect of
CYP3A5
genotype (
CYP3A5*3
and
*6
alleles), age, azoles, and corticosteroids on TAC trough concentration normalized for dose (TAC Co/D ng/ml/mg/kg/day) was assessed using a linear mixed model.
Results
Over time, TAC Co/D was lower in recipients with
CYP3A5*1/*3
genotype compared to those with
CYP3A5*3/*3
genotype (44.5 ± 14.4 vs. 107.6 ± 6.4,
p
= 0.03), increased in patients >12 years of age compared to < 12 years (93.9 ± 8.7 vs. 53.1 ± 12.9,
p
= 0.007), and decreased by concomitant corticosteroids (69.5 ± 12.7 vs. 89.9 ± 20.0,
p
= 0.04). The observed increased TAC Co/D in the presence of azoles (271 ± 41 vs. 111 ± 91,
p
= 0.016) could be attributed to clotrimazole.
Conclusions
Multiple factors, including
CYP3A5
genotype, and age, influence TAC Co/D in pediatric kidney transplant recipients. Clotrimazole administered as troches also contribute to TAC Co/D variability.</description><subject>Adolescent</subject><subject>Adrenal Cortex Hormones - therapeutic use</subject><subject>Age</subject><subject>Age Factors</subject><subject>Anti-Infective Agents, Local - therapeutic use</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Clotrimazole - therapeutic use</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 CYP3A - genetics</subject><subject>Dosage and administration</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Enzymes</subject><subject>Female</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Immunosuppressive Agents - blood</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Infant</subject><subject>Influence</subject><subject>Kidney failure</subject><subject>Kidney Transplantation</subject><subject>Kidney transplants</subject><subject>Kidneys</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolism</subject><subject>Nephrology</subject><subject>Original Article</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Retrospective Studies</subject><subject>Steroids</subject><subject>Tacrolimus</subject><subject>Tacrolimus - blood</subject><subject>Tacrolimus - therapeutic use</subject><subject>Toxicity</subject><subject>Transplantation</subject><subject>Urology</subject><subject>Young Adult</subject><issn>0931-041X</issn><issn>1432-198X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kl9rFDEUxYModq1-AF8kIBQfOjXJTDIzj8tS_0BBHxTqU8hmbnZTMsmYZB7qpzfjVm1lJQ-B3N-53HtyEHpJyQUlpH2bCGlEWxHaVKxjbcUeoRVtalbRvrt-jFakr2lFGnp9gp6ldEMI6XgnnqIT1nQtZy1bof2lMaAzDgZvvn2u1xzvwId8O8E5ThlisEM6x8oPWP0IDhIOHmelY3B2nBO2His8wWBVjlbjCF45nKPyaXLKZzyFaXYq2-CfoydGuQQv7u5T9PXd5ZfNh-rq0_uPm_VVpXlDc8UoB9rqXnBNBrIVPZBaDEMZeMsZ6zjVhIu6Z4Z3lLS06YfGCEGZHpTpaIFP0ZtD3ymG7zOkLEebNLgyDoQ5SVrkRFDRtgV9_Q96E-ZYNvhFsVrwnrG_1E45kNabUPbTS1O5rrumqfuWdIWqjlDFS4jKBQ_GlucH_MURvpwBRquPCs7uCfagXN6n4ObF2_QQpAewfFJKEYycoh1VvJWUyCU28hAbWWIjl9jIZcdXd07M2xGGP4rfOSkAOwCplPwO4j2r_tv1JzHQyJg</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Lalan, Shwetal</creator><creator>Abdel-Rahman, Susan</creator><creator>Gaedigk, Andrea</creator><creator>Leeder, J. Steven</creator><creator>Warady, Bradley A.</creator><creator>Dai, Hongying</creator><creator>Blowey, Douglas</creator><general>Springer Berlin Heidelberg</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>7QP</scope><scope>7RV</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>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope></search><sort><creationdate>20141001</creationdate><title>Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population</title><author>Lalan, Shwetal ; Abdel-Rahman, Susan ; Gaedigk, Andrea ; Leeder, J. Steven ; Warady, Bradley A. ; Dai, Hongying ; Blowey, Douglas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-215e17c965c0d0b69e036dd248b522851c056392f58107149d4f6612cdaf81e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adolescent</topic><topic>Adrenal Cortex Hormones - therapeutic use</topic><topic>Age</topic><topic>Age Factors</topic><topic>Anti-Infective Agents, Local - therapeutic use</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Clotrimazole - therapeutic use</topic><topic>Cytochrome</topic><topic>Cytochrome P-450 CYP3A - genetics</topic><topic>Dosage and administration</topic><topic>Drug dosages</topic><topic>Drug therapy</topic><topic>Enzymes</topic><topic>Female</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>Immunosuppressive Agents - blood</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Infant</topic><topic>Influence</topic><topic>Kidney failure</topic><topic>Kidney Transplantation</topic><topic>Kidney transplants</topic><topic>Kidneys</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolism</topic><topic>Nephrology</topic><topic>Original Article</topic><topic>Patients</topic><topic>Pediatrics</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Retrospective Studies</topic><topic>Steroids</topic><topic>Tacrolimus</topic><topic>Tacrolimus - blood</topic><topic>Tacrolimus - therapeutic use</topic><topic>Toxicity</topic><topic>Transplantation</topic><topic>Urology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lalan, Shwetal</creatorcontrib><creatorcontrib>Abdel-Rahman, Susan</creatorcontrib><creatorcontrib>Gaedigk, Andrea</creatorcontrib><creatorcontrib>Leeder, J. Steven</creatorcontrib><creatorcontrib>Warady, Bradley A.</creatorcontrib><creatorcontrib>Dai, Hongying</creatorcontrib><creatorcontrib>Blowey, Douglas</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>Calcium & Calcified Tissue Abstracts</collection><collection>Proquest Nursing & Allied Health Source</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 Essentials</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>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Consumer Health Database</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>MEDLINE - Academic</collection><jtitle>Pediatric nephrology (Berlin, West)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lalan, Shwetal</au><au>Abdel-Rahman, Susan</au><au>Gaedigk, Andrea</au><au>Leeder, J. Steven</au><au>Warady, Bradley A.</au><au>Dai, Hongying</au><au>Blowey, Douglas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population</atitle><jtitle>Pediatric nephrology (Berlin, West)</jtitle><stitle>Pediatr Nephrol</stitle><addtitle>Pediatr Nephrol</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>29</volume><issue>10</issue><spage>2039</spage><epage>2049</epage><pages>2039-2049</pages><issn>0931-041X</issn><eissn>1432-198X</eissn><abstract>Background
Numerous studies have described the impact of cytochrome P450 3A5 (
CYP3A5
) genotype on Tacrolimus (TAC) exposure. The purpose of this study was to conduct a comprehensive analysis of genetic and non-genetic factors affecting the TAC dose–exposure relationship over the first year post pediatric renal transplant.
Methods
Data were collected retrospectively for the first year post-transplant in pediatric renal transplant patients receiving TAC maintenance immunosuppression. The effect of
CYP3A5
genotype (
CYP3A5*3
and
*6
alleles), age, azoles, and corticosteroids on TAC trough concentration normalized for dose (TAC Co/D ng/ml/mg/kg/day) was assessed using a linear mixed model.
Results
Over time, TAC Co/D was lower in recipients with
CYP3A5*1/*3
genotype compared to those with
CYP3A5*3/*3
genotype (44.5 ± 14.4 vs. 107.6 ± 6.4,
p
= 0.03), increased in patients >12 years of age compared to < 12 years (93.9 ± 8.7 vs. 53.1 ± 12.9,
p
= 0.007), and decreased by concomitant corticosteroids (69.5 ± 12.7 vs. 89.9 ± 20.0,
p
= 0.04). The observed increased TAC Co/D in the presence of azoles (271 ± 41 vs. 111 ± 91,
p
= 0.016) could be attributed to clotrimazole.
Conclusions
Multiple factors, including
CYP3A5
genotype, and age, influence TAC Co/D in pediatric kidney transplant recipients. Clotrimazole administered as troches also contribute to TAC Co/D variability.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24875272</pmid><doi>10.1007/s00467-014-2827-2</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0931-041X |
| ispartof | Pediatric nephrology (Berlin, West), 2014-10, Vol.29 (10), p.2039-2049 |
| issn | 0931-041X 1432-198X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1563061677 |
| source | MEDLINE; SpringerNature Journals |
| subjects | Adolescent Adrenal Cortex Hormones - therapeutic use Age Age Factors Anti-Infective Agents, Local - therapeutic use Child Child, Preschool Clotrimazole - therapeutic use Cytochrome Cytochrome P-450 CYP3A - genetics Dosage and administration Drug dosages Drug therapy Enzymes Female Genotype Genotype & phenotype Humans Immunosuppressive Agents - blood Immunosuppressive Agents - therapeutic use Infant Influence Kidney failure Kidney Transplantation Kidney transplants Kidneys Male Medicine Medicine & Public Health Metabolism Nephrology Original Article Patients Pediatrics Polymorphism, Single Nucleotide Retrospective Studies Steroids Tacrolimus Tacrolimus - blood Tacrolimus - therapeutic use Toxicity Transplantation Urology Young Adult |
| title | Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population |
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