Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases
Identifieur interne : 001130 ( Istex/Corpus ); précédent : 001129; suivant : 001131Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases
Auteurs : Matthias Bu Chler ; Steve Chadban ; Edward Cole ; Karsten Midtvedt ; Eric Thervet ; Hans Prestele ; Paul KeownSource :
- Nephrology Dialysis Transplantation [ 0931-0509 ] ; 2006-01.
English descriptors
- KwdEn :
- Absorption profile, Acute rejection, Allograft recipients, Baseline characteristics, Blood concentration, Blood levels, Blood samples, C2 monitoring, Central laboratory, Clinical immunology, Cyclosporine, Cyclosporine microemulsion, International neoral, Kidney transplantation, Kilogram body weight, Microemulsion, Mo2art, Mo2art study, Mycophenolate mofetil, Neoral, Nephrol dial transplant, Pharmacokinetic, Pharmacokinetic parameters, Renal, Renal transplant patients, Renal transplant recipients, Renal transplantation, Steroid, Target group, Therapeutic drug monitoring, Transplant, Transplant patients, Transplant proc, Transplant recipients, Transplantation, Transplantation study group, Trough levels, Wilcoxon rank, absorption, cyclosporine microemulsion, renal transplantation.
- Teeft :
- Absorption profile, Acute rejection, Allograft recipients, Baseline characteristics, Blood concentration, Blood levels, Blood samples, Central laboratory, Clinical immunology, Cyclosporine, Cyclosporine microemulsion, International neoral, Kidney transplantation, Kilogram body weight, Microemulsion, Mo2art, Mo2art study, Mycophenolate mofetil, Neoral, Nephrol dial transplant, Pharmacokinetic, Pharmacokinetic parameters, Renal, Renal transplant patients, Renal transplant recipients, Renal transplantation, Steroid, Target group, Therapeutic drug monitoring, Transplant, Transplant patients, Transplant proc, Transplant recipients, Transplantation, Transplantation study group, Trough levels, Wilcoxon rank.
Abstract
Background. Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. Methods. Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. Results. C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C2/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01). Conclusions. CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.
Url:
DOI: 10.1093/ndt/gfi113
Links to Exploration step
ISTEX:5B276E4D1C60DD49B003B96C623017CA41E3D66ELe document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title><author><name sortKey="Bu Chler, Matthias" sort="Bu Chler, Matthias" uniqKey="Bu Chler M" first="Matthias" last="Bu Chler">Matthias Bu Chler</name><affiliation><mods:affiliation>Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France,</mods:affiliation></affiliation></author><author><name sortKey="Chadban, Steve" sort="Chadban, Steve" uniqKey="Chadban S" first="Steve" last="Chadban">Steve Chadban</name><affiliation><mods:affiliation>Royal Prince Alfred Hospital, Sydney, Australia,</mods:affiliation></affiliation></author><author><name sortKey="Cole, Edward" sort="Cole, Edward" uniqKey="Cole E" first="Edward" last="Cole">Edward Cole</name><affiliation><mods:affiliation>Renal Transplant Program, Toronto General Hospital, Toronto, Canada,</mods:affiliation></affiliation></author><author><name sortKey="Midtvedt, Karsten" sort="Midtvedt, Karsten" uniqKey="Midtvedt K" first="Karsten" last="Midtvedt">Karsten Midtvedt</name><affiliation><mods:affiliation>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway,</mods:affiliation></affiliation></author><author><name sortKey="Thervet, Eric" sort="Thervet, Eric" uniqKey="Thervet E" first="Eric" last="Thervet">Eric Thervet</name><affiliation><mods:affiliation>Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France,</mods:affiliation></affiliation></author><author><name sortKey="Prestele, Hans" sort="Prestele, Hans" uniqKey="Prestele H" first="Hans" last="Prestele">Hans Prestele</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland and</mods:affiliation></affiliation></author><author><name sortKey="Keown, Paul" sort="Keown, Paul" uniqKey="Keown P" first="Paul" last="Keown">Paul Keown</name><affiliation><mods:affiliation>Department of Medicine, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:5B276E4D1C60DD49B003B96C623017CA41E3D66E</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1093/ndt/gfi113</idno><idno type="url">https://api.istex.fr/document/5B276E4D1C60DD49B003B96C623017CA41E3D66E/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001130</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001130</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title><author><name sortKey="Bu Chler, Matthias" sort="Bu Chler, Matthias" uniqKey="Bu Chler M" first="Matthias" last="Bu Chler">Matthias Bu Chler</name><affiliation><mods:affiliation>Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France,</mods:affiliation></affiliation></author><author><name sortKey="Chadban, Steve" sort="Chadban, Steve" uniqKey="Chadban S" first="Steve" last="Chadban">Steve Chadban</name><affiliation><mods:affiliation>Royal Prince Alfred Hospital, Sydney, Australia,</mods:affiliation></affiliation></author><author><name sortKey="Cole, Edward" sort="Cole, Edward" uniqKey="Cole E" first="Edward" last="Cole">Edward Cole</name><affiliation><mods:affiliation>Renal Transplant Program, Toronto General Hospital, Toronto, Canada,</mods:affiliation></affiliation></author><author><name sortKey="Midtvedt, Karsten" sort="Midtvedt, Karsten" uniqKey="Midtvedt K" first="Karsten" last="Midtvedt">Karsten Midtvedt</name><affiliation><mods:affiliation>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway,</mods:affiliation></affiliation></author><author><name sortKey="Thervet, Eric" sort="Thervet, Eric" uniqKey="Thervet E" first="Eric" last="Thervet">Eric Thervet</name><affiliation><mods:affiliation>Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France,</mods:affiliation></affiliation></author><author><name sortKey="Prestele, Hans" sort="Prestele, Hans" uniqKey="Prestele H" first="Hans" last="Prestele">Hans Prestele</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland and</mods:affiliation></affiliation></author><author><name sortKey="Keown, Paul" sort="Keown, Paul" uniqKey="Keown P" first="Paul" last="Keown">Paul Keown</name><affiliation><mods:affiliation>Department of Medicine, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Nephrology Dialysis Transplantation</title><title level="j" type="abbrev">Nephrol. Dial. Transplant.</title><idno type="ISSN">0931-0509</idno><idno type="eISSN">1460-2385</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-01">2006-01</date><biblScope unit="volume">21</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="197">197</biblScope><biblScope unit="page" to="202">202</biblScope></imprint><idno type="ISSN">0931-0509</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0931-0509</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Absorption profile</term><term>Acute rejection</term><term>Allograft recipients</term><term>Baseline characteristics</term><term>Blood concentration</term><term>Blood levels</term><term>Blood samples</term><term>C2 monitoring</term><term>Central laboratory</term><term>Clinical immunology</term><term>Cyclosporine</term><term>Cyclosporine microemulsion</term><term>International neoral</term><term>Kidney transplantation</term><term>Kilogram body weight</term><term>Microemulsion</term><term>Mo2art</term><term>Mo2art study</term><term>Mycophenolate mofetil</term><term>Neoral</term><term>Nephrol dial transplant</term><term>Pharmacokinetic</term><term>Pharmacokinetic parameters</term><term>Renal</term><term>Renal transplant patients</term><term>Renal transplant recipients</term><term>Renal transplantation</term><term>Steroid</term><term>Target group</term><term>Therapeutic drug monitoring</term><term>Transplant</term><term>Transplant patients</term><term>Transplant proc</term><term>Transplant recipients</term><term>Transplantation</term><term>Transplantation study group</term><term>Trough levels</term><term>Wilcoxon rank</term><term>absorption</term><term>cyclosporine microemulsion</term><term>renal transplantation</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Absorption profile</term><term>Acute rejection</term><term>Allograft recipients</term><term>Baseline characteristics</term><term>Blood concentration</term><term>Blood levels</term><term>Blood samples</term><term>Central laboratory</term><term>Clinical immunology</term><term>Cyclosporine</term><term>Cyclosporine microemulsion</term><term>International neoral</term><term>Kidney transplantation</term><term>Kilogram body weight</term><term>Microemulsion</term><term>Mo2art</term><term>Mo2art study</term><term>Mycophenolate mofetil</term><term>Neoral</term><term>Nephrol dial transplant</term><term>Pharmacokinetic</term><term>Pharmacokinetic parameters</term><term>Renal</term><term>Renal transplant patients</term><term>Renal transplant recipients</term><term>Renal transplantation</term><term>Steroid</term><term>Target group</term><term>Therapeutic drug monitoring</term><term>Transplant</term><term>Transplant patients</term><term>Transplant proc</term><term>Transplant recipients</term><term>Transplantation</term><term>Transplantation study group</term><term>Trough levels</term><term>Wilcoxon rank</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background. Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. Methods. Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. Results. C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C2/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01). Conclusions. CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.</div></front></TEI><istex><corpusName>oup</corpusName><keywords><teeft><json:string>cyclosporine</json:string><json:string>transplantation</json:string><json:string>pharmacokinetic</json:string><json:string>renal</json:string><json:string>neoral</json:string><json:string>microemulsion</json:string><json:string>transplant</json:string><json:string>pharmacokinetic parameters</json:string><json:string>cyclosporine microemulsion</json:string><json:string>mo2art</json:string><json:string>steroid</json:string><json:string>renal transplantation</json:string><json:string>renal transplant recipients</json:string><json:string>renal transplant patients</json:string><json:string>transplant patients</json:string><json:string>central laboratory</json:string><json:string>nephrol dial transplant</json:string><json:string>transplantation study group</json:string><json:string>transplant proc</json:string><json:string>blood samples</json:string><json:string>mo2art study</json:string><json:string>wilcoxon rank</json:string><json:string>therapeutic drug monitoring</json:string><json:string>mycophenolate mofetil</json:string><json:string>acute rejection</json:string><json:string>blood levels</json:string><json:string>baseline characteristics</json:string><json:string>target group</json:string><json:string>absorption profile</json:string><json:string>kilogram body weight</json:string><json:string>blood concentration</json:string><json:string>trough levels</json:string><json:string>international neoral</json:string><json:string>clinical immunology</json:string><json:string>transplant recipients</json:string><json:string>allograft recipients</json:string><json:string>kidney transplantation</json:string></teeft></keywords><author><json:item><name>Matthias Büchler</name><affiliations><json:string>Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France,</json:string></affiliations></json:item><json:item><name>Steve Chadban</name><affiliations><json:string>Royal Prince Alfred Hospital, Sydney, Australia,</json:string></affiliations></json:item><json:item><name>Edward Cole</name><affiliations><json:string>Renal Transplant Program, Toronto General Hospital, Toronto, Canada,</json:string></affiliations></json:item><json:item><name>Karsten Midtvedt</name><affiliations><json:string>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway,</json:string></affiliations></json:item><json:item><name>Eric Thervet</name><affiliations><json:string>Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France,</json:string></affiliations></json:item><json:item><name>Hans Prestele</name><affiliations><json:string>Novartis Pharma AG, Basel, Switzerland and</json:string></affiliations></json:item><json:item><name>Paul Keown</name><affiliations><json:string>Department of Medicine, University of British Columbia, Vancouver, Canada</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>absorption</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>C2 monitoring</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cyclosporine microemulsion</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>renal transplantation</value></json:item></subject><arkIstex>ark:/67375/HXZ-9PH1GM9F-Z</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>other</json:string></originalGenre><abstract>Background. Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. Methods. Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. Results. C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C2/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P>0.05) and at 12 months (48 vs 31%, P>0.01). Conclusions. CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.</abstract><qualityIndicators><score>8.209</score><pdfWordCount>3221</pdfWordCount><pdfCharCount>21154</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>6</pdfPageCount><pdfPageSize>595 x 782 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>249</abstractWordCount><abstractCharCount>1590</abstractCharCount><keywordCount>4</keywordCount></qualityIndicators><title>Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title><pmid><json:string>16204301</json:string></pmid><genre><json:string>other</json:string></genre><host><title>Nephrology Dialysis Transplantation</title><language><json:string>unknown</json:string></language><issn><json:string>0931-0509</json:string></issn><eissn><json:string>1460-2385</json:string></eissn><publisherId><json:string>ndt</json:string></publisherId><volume>21</volume><issue>1</issue><pages><first>197</first><last>202</last></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Original Articles: Dialysis and Transplantation</value></json:item></subject></host><namedEntities><unitex><date><json:string>2005-10-04</json:string></date><geogName></geogName><orgName><json:string>Department of Renal Transplantation and Intensive Care</json:string><json:string>Department of Nephrology and Clinical Immunology</json:string><json:string>Toronto General Hospital, Toronto, Canada</json:string><json:string>Department of Medicine, University of British Columbia, Vancouver, Canada Abstract Background</json:string><json:string>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway</json:string><json:string>Oxford University</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>E. Cole</json:string><json:string>Alfred Hospital</json:string><json:string>Hans Prestele</json:string><json:string>Steve Chadban</json:string><json:string>H. Prestele</json:string><json:string>K. Midtvedt</json:string><json:string>E. Thervet</json:string><json:string>S. Chapman</json:string><json:string>C.H.U. Tours</json:string><json:string>Paul Keown</json:string><json:string>Matthias Buchler</json:string><json:string>Eric Thervet</json:string><json:string>Edward Cole</json:string><json:string>Karsten Midtvedt</json:string></persName><placeName><json:string>Paris</json:string><json:string>Switzerland</json:string><json:string>Australia</json:string><json:string>Basel</json:string><json:string>France</json:string><json:string>Sydney</json:string><json:string>Tours</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[7,8]</json:string><json:string>Midtvedt et al. [20]</json:string><json:string>[18]</json:string><json:string>[6]</json:string><json:string>[17]</json:string><json:string>[1]</json:string><json:string>[16]</json:string><json:string>[4,14]</json:string><json:string>[20]</json:string><json:string>Lemahieu et al. [21]</json:string><json:string>[5]</json:string><json:string>[15]</json:string><json:string>M. Buchler et al.</json:string><json:string>[7]</json:string><json:string>[6,15]</json:string><json:string>[2005]</json:string><json:string>[19]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-9PH1GM9F-Z</json:string></ark><categories><wos><json:string>science</json:string><json:string>urology & nephrology</json:string><json:string>transplantation</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>urology & nephrology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Transplantation</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Nephrology</json:string></scopus><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2006</publicationDate><copyrightDate>2006</copyrightDate><doi><json:string>10.1093/ndt/gfi113</json:string></doi><id>5B276E4D1C60DD49B003B96C623017CA41E3D66E</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/5B276E4D1C60DD49B003B96C623017CA41E3D66E/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/5B276E4D1C60DD49B003B96C623017CA41E3D66E/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/5B276E4D1C60DD49B003B96C623017CA41E3D66E/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">Oxford University Press</publisher><availability><licence><p>© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</p></availability><date>2005-10-04</date></publicationStmt><notesStmt><note type="other" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-7474895G-0">other</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note>Correspondence and offprint requests to: Dr Matthias Büchler, Department of Nephrology and Clinical Immunology, C.H.U. Tours, 2 Boulevard Tonnellé 37044 Tours, France. Email: buchler@med.univ-tours.fr</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title><author xml:id="author-0000"><persName><forename type="first">Matthias</forename><surname>Büchler</surname></persName><affiliation>Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France,</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Steve</forename><surname>Chadban</surname></persName><affiliation>Royal Prince Alfred Hospital, Sydney, Australia,</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Edward</forename><surname>Cole</surname></persName><affiliation>Renal Transplant Program, Toronto General Hospital, Toronto, Canada,</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Karsten</forename><surname>Midtvedt</surname></persName><affiliation>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway,</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Eric</forename><surname>Thervet</surname></persName><affiliation>Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France,</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Hans</forename><surname>Prestele</surname></persName><affiliation>Novartis Pharma AG, Basel, Switzerland and</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Paul</forename><surname>Keown</surname></persName><affiliation>Department of Medicine, University of British Columbia, Vancouver, Canada</affiliation></author><idno type="istex">5B276E4D1C60DD49B003B96C623017CA41E3D66E</idno><idno type="ark">ark:/67375/HXZ-9PH1GM9F-Z</idno><idno type="DOI">10.1093/ndt/gfi113</idno><idno type="local">gfi113</idno></analytic><monogr><title level="j">Nephrology Dialysis Transplantation</title><title level="j" type="abbrev">Nephrol. Dial. Transplant.</title><idno type="pISSN">0931-0509</idno><idno type="eISSN">1460-2385</idno><idno type="publisher-id">ndt</idno><idno type="PublisherID-hwp">ndt</idno><idno type="PublisherID-nlm-ta">Nephrol Dial Transplant</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-01"></date><biblScope unit="volume">21</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="197">197</biblScope><biblScope unit="page" to="202">202</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005-10-04</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Background. Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. Methods. Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. Results. C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C2/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01). Conclusions. CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>absorption</term></item><item><term>C2 monitoring</term></item><item><term>cyclosporine microemulsion</term></item><item><term>renal transplantation</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>Original Articles: Dialysis and Transplantation</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2005-10-04">Created</change><change when="2006-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/5B276E4D1C60DD49B003B96C623017CA41E3D66E/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="other">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">ndt</journal-id>
<journal-id journal-id-type="nlm-ta">Nephrol Dial Transplant</journal-id>
<journal-id journal-id-type="publisher-id">ndt</journal-id>
<journal-title>Nephrology Dialysis Transplantation</journal-title>
<abbrev-journal-title abbrev-type="publisher">Nephrol. Dial. Transplant.</abbrev-journal-title>
<issn pub-type="ppub">0931-0509</issn>
<issn pub-type="epub">1460-2385</issn>
<publisher>
<publisher-name>Oxford University Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="other">gfi113</article-id>
<article-id pub-id-type="doi">10.1093/ndt/gfi113</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>II. Scientific Papers</subject>
<subj-group>
<subject>Original Articles: Dialysis and Transplantation</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the <italic>de novo</italic> and maintenance phases</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Büchler</surname>
<given-names>Matthias</given-names>
</name>
<xref rid="AFF1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chadban</surname>
<given-names>Steve</given-names>
</name>
<xref rid="AFF2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cole</surname>
<given-names>Edward</given-names>
</name>
<xref rid="AFF3">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Midtvedt</surname>
<given-names>Karsten</given-names>
</name>
<xref rid="AFF4">
<sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Thervet</surname>
<given-names>Eric</given-names>
</name>
<xref rid="AFF5">
<sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Prestele</surname>
<given-names>Hans</given-names>
</name>
<xref rid="AFF6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Keown</surname>
<given-names>Paul</given-names>
</name>
<xref rid="AFF7">
<sup>7</sup>
</xref>
</contrib>
<aff><target target-type="aff" id="AFF1"></target><label>1</label>Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France, <target target-type="aff" id="AFF2"></target><label>2</label>Royal Prince Alfred Hospital, Sydney, Australia, <target target-type="aff" id="AFF3"></target><label>3</label>Renal Transplant Program, Toronto General Hospital, Toronto, Canada, <target target-type="aff" id="AFF4"></target><label>4</label>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway, <target target-type="aff" id="AFF5"></target><label>5</label>Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France, <target target-type="aff" id="AFF6"></target><label>6</label>Novartis Pharma AG, Basel, Switzerland and <target target-type="aff" id="AFF7"></target><label>7</label>Department of Medicine, University of British Columbia, Vancouver, Canada</aff>
</contrib-group>
<author-notes>
<corresp><italic>Correspondence and offprint requests to</italic>: Dr Matthias Büchler, Department of Nephrology and Clinical Immunology, C.H.U. Tours, 2 Boulevard Tonnellé 37044 Tours, France. Email: <ext-link xlink:href="buchler@med.univ-tours.fr" ext-link-type="email">buchler@med.univ-tours.fr</ext-link></corresp>
</author-notes>
<pub-date pub-type="epub">
<day>4</day>
<month>10</month>
<year>2005</year>
</pub-date>
<pub-date pub-type="ppub">
<month>January</month>
<year>2006</year>
</pub-date>
<volume>21</volume>
<issue>1</issue>
<fpage>197</fpage>
<lpage>202</lpage>
<history>
<date date-type="accepted">
<day>8</day>
<month>8</month>
<year>2005</year>
</date>
<date date-type="received">
<day>21</day>
<month>4</month>
<year>2005</year>
</date>
</history>
<permissions>
<copyright-statement>© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement>
<copyright-year>2006</copyright-year>
</permissions>
<abstract xml:lang="en">
<p><bold>Background.</bold> Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C<sub>0</sub>) or levels at 2 h post-dose (C<sub>2</sub>). This analysis assessed changes in C<sub>0</sub> and C<sub>2</sub> and their relationship to CsA-ME dose over time post-transplant in renal transplant patients.</p>
<p><bold>Methods.</bold> Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C<sub>2</sub> level. All 98 patients in whom C<sub>0</sub> and C<sub>2</sub> were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C<sub>0</sub>/ND, C<sub>2</sub>/ND and C<sub>2</sub>/C<sub>0</sub>.</p>
<p><bold>Results.</bold> C<sub>0</sub>/ND and C<sub>2</sub>/ND both increased between day 5 and month 3: C<sub>0</sub>/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C<sub>2</sub>/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C<sub>2</sub>/ND remained stable but C<sub>0</sub>/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C<sub>2</sub>/C<sub>0</sub> ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C<sub>0</sub>/ND than for C<sub>2</sub>/ND at 3 months (45 <italic>vs</italic> 32%, <italic>P</italic><0.05) and at 12 months (48 <italic>vs</italic> 31%, <italic>P</italic><0.01).</p>
<p><bold>Conclusions.</bold> CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C<sub>0</sub> levels for a given exposure (as measured by C<sub>2</sub>). As a consequence, C<sub>0</sub> monitoring may progressively underestimate CsA exposure during the first year post-transplant. C<sub>2</sub> monitoring contributes to improved individualized CsA-ME treatment in both the <italic>de novo</italic> phase and beyond month 3.</p>
</abstract>
<kwd-group kwd-group-type="KWD" xml:lang="en">
<kwd>absorption</kwd>
<kwd>C<sub>2</sub> monitoring</kwd>
<kwd>cyclosporine microemulsion</kwd>
<kwd>renal transplantation</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>hwp-legacy-fpage</meta-name>
<meta-value>197</meta-value>
</custom-meta>
<custom-meta>
<meta-name>cover-date</meta-name>
<meta-value>January 2006</meta-value>
</custom-meta>
<custom-meta>
<meta-name>hwp-legacy-dochead</meta-name>
<meta-value>Original Articles: Dialysis and Transplantation</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec>
<title>Introduction</title>
<p>Recent years have seen an intensive research effort directed towards improving the therapeutic drug monitoring of immunosuppressive agents [<xref rid="BIB1">1</xref>]. In particular, attention has focused on cyclosporine (CsA) [<xref rid="BIB2">2–4</xref><xref rid="BIB3"></xref><xref rid="BIB4"></xref>], with the goal of ensuring appropriate CsA exposure in individual recipients of solid organ transplants.</p>
<p>Inter-patient variability in CsA blood levels is highest within the first 4 h post-dose, when CsA absorption predominates. CsA exposure within the first 4 h (AUC<sub>0–4</sub>) after administration of cyclosporine microemulsion (CsA-ME) is predictive of acute cellular rejection within the first 3 months post-transplantation [<xref rid="BIB5">5</xref>]. CsA blood concentration 2 h after dosing (C<sub>2</sub>) is the single time-point that correlates most closely with AUC<sub>0–4</sub>, and C<sub>2</sub> values have been shown to correlate with inhibition of calcineurin [<xref rid="BIB6">6</xref>] and risk of acute rejection [<xref rid="BIB7">7</xref>]. In contrast, conventional trough (C<sub>0</sub>) measurements of CsA blood concentration correlate only poorly with AUC<sub>0–4</sub> [<xref rid="BIB7">7</xref>,<xref rid="BIB8">8</xref>] and C<sub>0</sub> is not a sensitive marker for risk of rejection [<xref rid="BIB5">5</xref>]. Nevertheless, C<sub>0</sub> monitoring is still used in many transplant centres because adoption of C<sub>2</sub> monitoring requires logistical changes within transplant units, and because blood samples for C<sub>2</sub> monitoring must be collected within a 30 min window (i.e. 2 h±15 min post-dose).</p>
<p>More recently, some authors have argued that a combination of C<sub>2</sub> and C<sub>0</sub> monitoring could be a useful technique for evaluating the absorption profile of cyclosporine more precisely, since it takes into account both the absorption phase (C<sub>2</sub>) and the elimination phase, including metabolism (C<sub>0</sub>). The C<sub>2</sub>/C<sub>0</sub> ratio has also been used to identify high or low absorbers of CsA [<xref rid="BIB10">10</xref>].</p>
<p>Finally, several studies have evaluated the influence of the intra-individual coefficient of variation of either the C<sub>0</sub> or C<sub>2</sub> on clinical events [<xref rid="BIB11">11–13</xref><xref rid="BIB12"></xref><xref rid="BIB13"></xref>]. However, most of these trials had important limitations, notably use of the oil-based formulation of CsA and recording pharmacokinetic parameters at variable time-points.</p>
<p>The aim of our study was to analyse changes in pharmacokinetic parameters for CsA-ME over the first year post-transplant in renal transplant patients. We analysed C<sub>2</sub> and C<sub>0</sub> together with their relationship to the weight-adjusted dose of CsA-ME and to each other. Additionally, we studied the intra-individual stability of these parameters and the inter-individual coefficient of variation up to 1 year post-transplant.</p>
</sec>
<sec>
<title>Subjects and methods</title>
<p>The analysis was based on data collected in the MO2ART study (Monitoring Of 2 hours Absorption in Renal Transplantation), a prospective, randomized, multicentre study in which <italic>de novo</italic> renal transplant patients were managed by C<sub>2</sub> monitoring of CsA-ME. Details of the study design and findings have been published previously [<xref rid="BIB4">4</xref>,<xref rid="BIB14">14</xref>]. All patients received CsA-ME b.i.d., starting within 24 h post-transplantation at a dose of 10 mg/kg, in conjunction with steroids and mycophenolate mofetil or azathioprine. The C<sub>2</sub> target was 1600–2000 ng/ml during month 1 and 1200–1400 ng/ml for months 2 and 3. At the end of month 3, patients entered randomized groups in which C<sub>2</sub> targets were lower (800–1000 ng/ml during months 4–6; 600–800 ng/ml during months 7–12) or higher (1000–1200 ng/ml during months 4–6; 800–1000 ng/ml during months 7–12). Blood samples for the central laboratory were collected before dosing (C<sub>0</sub>) and 2 h post-dose (C<sub>2</sub>) on day 5 and at months 3 and 12. CsA concentrations were determined using the specific reagents of the INCSTAR Cyclo-Trac® SP-Whole Blood radioimmunoassay kit, based on whole-blood samples. CsA-ME dose, body weight and other parameters including locally determined laboratory values were obtained from the MO2ART database for each of the three time-points.</p>
<p>The analysis included all 98 patients for whom centrally determined values for C<sub>0</sub> and C<sub>2</sub> were available at day 5, month 3 and month 12. At each time-point we calculated the CsA-ME dose per kilogram body weight (normalized dose, ND), and the ratios C<sub>0</sub>/ND, C<sub>2</sub>/ND and C<sub>2</sub>/C<sub>0</sub>. The interpatient coefficient of variance (CV) for C<sub>0</sub>/ND and C<sub>2</sub>/ND was calculated across all patients at each of the three time-points. Intra-individual CVs were not calculated because only two samples per patient were available for the maintenance period (months 3 and 12). Instead, intra-individual stability was assessed by calculating individual ratios between the month 3 and month 12 values for C<sub>0</sub>/ND, C<sub>2</sub>/ND and C<sub>2</sub>/C<sub>0</sub>.</p>
<p>Fisher's exact test, <italic>t</italic>-test and Wilcoxon rank sum test were used for between group comparisons. The paired <italic>t</italic>-test was used to compare intra-individual changes over time. To account for the different individual levels, relative changes from month 3 to month 12, in percentage of the month 3 values, were also determined. Confidence intervals were used for the assessment of the inter-patient CV.</p>
</sec>
<sec>
<title>Results</title>
<p>Two hundred and ninety-six patients were recruited to MO2ART. Of the 234 patients who completed the 12 month trial, 98 provided C<sub>0</sub> and C<sub>2</sub> blood samples on day 5, month 3 and month 12 to the central laboratory and were included in this analysis. No reason could be found why incomplete or no samples were provided for the remaining patients, other than centre non-compliance, and there were no significant differences in demographics or baseline characteristics between patients who completed the study and did or did not provide a full set of blood samples (<xref rid="TBL1">Table 1</xref>). Of the included patients, 91 started on mycophenolate mofetil and 7 on azathioprine as an adjunctive agent. Patients with delayed graft function (DGF) were less likely to continue the study until month 12 than those with immediate function (67 <italic>vs</italic> 86%), such that the proportion of patients with DGF was lower in our cohort than the overall MO2ART study population.
<table-wrap id="TBL1" position="float"><label><bold>Table 1.</bold></label><caption><p>Patient demographics and baseline characteristics of patients completing the 12-month MO2ART study, according to inclusion or exclusion from current analysis</p></caption><table><thead><tr><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top">Patients included<xref rid="TBLFN1"><sup>a</sup></xref> (<italic>n</italic> = 98)</th><th colspan="1" rowspan="1" align="left" valign="top">Patients excluded (<italic>n</italic> = 136)</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">Recipient age (years)</td><td colspan="1" rowspan="1" align="left" valign="top">>55</td><td colspan="1" rowspan="1" align="left" valign="top">45.9±12.820 (20%)</td><td colspan="1" rowspan="1" align="left" valign="top">44.4±13.129 (21%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Gender</td><td colspan="1" rowspan="1" align="left" valign="top">Male</td><td colspan="1" rowspan="1" align="left" valign="top">67 (68%)</td><td colspan="1" rowspan="1" align="left" valign="top">79 (58%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Female</td><td colspan="1" rowspan="1" align="left" valign="top">31 (32%)</td><td colspan="1" rowspan="1" align="left" valign="top">57 (42%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Recipient race</td><td colspan="1" rowspan="1" align="left" valign="top">Caucasian</td><td colspan="1" rowspan="1" align="left" valign="top">92 (94%)</td><td colspan="1" rowspan="1" align="left" valign="top">123 (90%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Black</td><td colspan="1" rowspan="1" align="left" valign="top">3 (3%)</td><td colspan="1" rowspan="1" align="left" valign="top">1 (1%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Oriental</td><td colspan="1" rowspan="1" align="left" valign="top">2 (2%)</td><td colspan="1" rowspan="1" align="left" valign="top">3 (2%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Other</td><td colspan="1" rowspan="1" align="left" valign="top">1 (1%)</td><td colspan="1" rowspan="1" align="left" valign="top">9 (7%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">DGF</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">27 (28%)</td><td colspan="1" rowspan="1" align="left" valign="top">45 (33%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Diabetic at baseline</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">5 (5%)</td><td colspan="1" rowspan="1" align="left" valign="top">8 (6%)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Weight at baseline (kg)</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">70.3±12.1</td><td colspan="1" rowspan="1" align="left" valign="top">71.6±14.2</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">GFR at month 12 (Cockcroft–Gault) (ml/min)</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">60.0±19.5</td><td colspan="1" rowspan="1" align="left" valign="top">59.2±19.2</td></tr></tbody></table><table-wrap-foot><fn><p>Continuous variables are shown as mean ± standard deviation; categorical variables are shown as number of patients. There were no significant differences in any parameter between the two populations.</p></fn><fn id="TBLFN1"><p><sup>a</sup>Patients were included if C<sub>0</sub> and C<sub>2</sub> blood samples were provided to the central laboratory on day 5, month 3 and month 12. Patients were excluded when incomplete or no samples were provided.</p></fn></table-wrap-foot></table-wrap></p>
<p>The dose of CsA-ME and CsA concentrations were greatest early post-transplant, declining thereafter in line with decreasing C<sub>2</sub> target ranges (<xref rid="FIG1">Figure 1</xref> and <xref rid="TBL2">Table 2</xref>). When the same analysis was undertaken separately for patients entering the higher-C<sub>2</sub> target group (59/98) or the lower-C<sub>2</sub> target group (39/98) after month 3, there were no differences compared with the overall analysis (<xref rid="TBL3">Table 3</xref>). The relationship between C<sub>0</sub> and C<sub>2</sub> levels and weight-normalized dose, expressed by C<sub>0</sub>/ND and C<sub>2</sub>/ND, increased significantly between day 5 and month 3 (<xref rid="TBL2">Table 2</xref> and <xref rid="FIG2">Figure 2</xref>). This was expected and confirms the well-known increase in drug absorption early after renal transplantation. Between month 3 and 12, CsA-ME dose as well as absolute C<sub>0</sub> and C<sub>2</sub> levels decreased further. While the relationship between C<sub>2</sub> and CsA-ME dose (C<sub>2</sub>/ND) remained stable (median −3%), the decrease of C<sub>0</sub> levels was more marked, resulting in a net decrease of C<sub>0</sub>/ND and an increase in the ratio of C<sub>2</sub>/C<sub>0</sub> (<xref rid="FIG2">Figure 2</xref> and <xref rid="TBL2">Table 2</xref>). This effect appeared not to be linked to the CsA-ME dose: when patients were stratified into tertiles according to weight-adjusted CsA-ME dose at month 12, the C<sub>2</sub>/C<sub>0</sub> ratio was 6.6±2.9, 6.2±1.9 and 6.8±2.2 for patients receiving <2.7, 2.7–3.5 or ≥3.5 mg/kg CsA-ME, respectively (n.s.).
<fig id="FIG1" position="float"><label><bold>Fig. 1.</bold></label><caption><p>Mean CsA-ME dose, mean C<sub>2</sub> and mean C<sub>0</sub> levels at day 5, month 3 and month 12 post-transplant (<italic>n</italic> = 98).</p></caption><graphic xlink:href="gfi113f1"></graphic></fig>
<fig id="FIG2" position="float"><label><bold>Fig. 2.</bold></label><caption><p>Distribution of pharmacokinetic parameters at day 5, month 3 and month 12 post-transplant (<italic>n</italic> = 98).</p></caption><graphic xlink:href="gfi113f2"></graphic></fig>
<table-wrap id="TBL2" position="float"><label><bold>Table 2.</bold></label><caption><p>Pharmacokinetic parameters at day 5, month 3 and month 12</p></caption><table><thead><tr><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top">Day 5</th><th colspan="1" rowspan="1" align="left" valign="top">Month 3</th><th colspan="1" rowspan="1" align="left" valign="top">Month 12</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">ND (mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">10.1±3.5</td><td colspan="1" rowspan="1" align="left" valign="top">5.0±1.4<xref rid="TBLFN2"><sup>a</sup></xref></td><td colspan="1" rowspan="1" align="left" valign="top">3.3±1.0<xref rid="TBLFN2"><sup>b</sup></xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>0</sub> (ng/ml)</td><td colspan="1" rowspan="1" align="left" valign="top">325±183</td><td colspan="1" rowspan="1" align="left" valign="top">258±117<xref rid="TBLFN2"><sup>a</sup></xref></td><td colspan="1" rowspan="1" align="left" valign="top">129±59<xref rid="TBLFN2"><sup>b</sup></xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub> (ng/ml)</td><td colspan="1" rowspan="1" align="left" valign="top">1530±561</td><td colspan="1" rowspan="1" align="left" valign="top">1203±378<xref rid="TBLFN2"><sup>a</sup></xref></td><td colspan="1" rowspan="1" align="left" valign="top">763±218<xref rid="TBLFN2"><sup>b</sup></xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>0</sub>/ND (ng/ml)/(mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">33±15</td><td colspan="1" rowspan="1" align="left" valign="top">53±24<xref rid="TBLFN2"><sup>a</sup></xref></td><td colspan="1" rowspan="1" align="left" valign="top">42±20<xref rid="TBLFN2"><sup>b</sup></xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">CV for C<sub>0</sub>/ND (%)</td><td colspan="1" rowspan="1" align="left" valign="top">45%</td><td colspan="1" rowspan="1" align="left" valign="top">45%</td><td colspan="1" rowspan="1" align="left" valign="top">48%</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub>/ND (ng/ml)/(mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">161±64</td><td colspan="1" rowspan="1" align="left" valign="top">248±80<xref rid="TBLFN2"><sup>a</sup></xref></td><td colspan="1" rowspan="1" align="left" valign="top">247±78</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">CV for C<sub>2</sub>/ND (%)</td><td colspan="1" rowspan="1" align="left" valign="top">40%</td><td colspan="1" rowspan="1" align="left" valign="top">32%</td><td colspan="1" rowspan="1" align="left" valign="top">31%</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub>/C<sub>0</sub></td><td colspan="1" rowspan="1" align="left" valign="top">5.8±3.1</td><td colspan="1" rowspan="1" align="left" valign="top">5.2±1.9</td><td colspan="1" rowspan="1" align="left" valign="top">6.5±2.3<xref rid="TBLFN2"><sup>b</sup></xref></td></tr></tbody></table><table-wrap-foot><fn><p>ND, normalized CsA-ME dose; CV, coefficient of variation.</p></fn><fn id="TBLFN2"><p><sup>a</sup><italic>P</italic><0.01 <italic>vs</italic> day 5; <sup>b</sup><italic>P</italic><0.01 <italic>vs</italic> month 3.</p></fn></table-wrap-foot></table-wrap>
<table-wrap id="TBL3" position="float"><label><bold>Table 3.</bold></label><caption><p>Pharmacokinetic parameters at month 3 and month 12 for patients in higher-C<sub>2</sub> cohort (<italic>n</italic> = 59) or lower-C<sub>2</sub> cohort (<italic>n</italic> = 39) after month 3</p></caption><table><thead><tr><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="3" rowspan="1" align="left" valign="top">Month 3<hr></hr></th><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="3" rowspan="1" align="left" valign="top">Month 12<hr></hr></th><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top"></th></tr><tr><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top">Lower-C<sub>2</sub></th><th colspan="1" rowspan="1" align="left" valign="top">Higher-C<sub>2</sub></th><th colspan="1" rowspan="1" align="left" valign="top"><italic>P</italic><xref rid="TBLFN3"><sup>a</sup></xref></th><th colspan="1" rowspan="1" align="left" valign="top">Lower-C<sub>2</sub></th><th colspan="1" rowspan="1" align="left" valign="top">Higher-C<sub>2</sub></th><th colspan="1" rowspan="1" align="left" valign="top"><italic>P</italic></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">ND (mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">4.8±1.4</td><td colspan="1" rowspan="1" align="left" valign="top">5.2±1.4</td><td colspan="1" rowspan="1" align="left" valign="top">0.286</td><td colspan="1" rowspan="1" align="left" valign="top">2.9±0.8</td><td colspan="1" rowspan="1" align="left" valign="top">3.5±1.0</td><td colspan="1" rowspan="1" align="left" valign="top">0.003</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>0</sub> (ng/ml)</td><td colspan="1" rowspan="1" align="left" valign="top">252±122</td><td colspan="1" rowspan="1" align="left" valign="top">262±115</td><td colspan="1" rowspan="1" align="left" valign="top">0.682</td><td colspan="1" rowspan="1" align="left" valign="top">120±59</td><td colspan="1" rowspan="1" align="left" valign="top">135±59</td><td colspan="1" rowspan="1" align="left" valign="top">0.059</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub> (ng/ml)</td><td colspan="1" rowspan="1" align="left" valign="top">1230±409</td><td colspan="1" rowspan="1" align="left" valign="top">1185±359</td><td colspan="1" rowspan="1" align="left" valign="top">0.392</td><td colspan="1" rowspan="1" align="left" valign="top">691±211</td><td colspan="1" rowspan="1" align="left" valign="top">810±211</td><td colspan="1" rowspan="1" align="left" valign="top">0.004</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>0</sub>/ND (ng/ml)/(mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">54±26</td><td colspan="1" rowspan="1" align="left" valign="top">53±23</td><td colspan="1" rowspan="1" align="left" valign="top">0.783</td><td colspan="1" rowspan="1" align="left" valign="top">44±20</td><td colspan="1" rowspan="1" align="left" valign="top">41±21</td><td colspan="1" rowspan="1" align="left" valign="top">0.48</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">CV for C<sub>0</sub>/ND (%)</td><td colspan="1" rowspan="1" align="left" valign="top">47%</td><td colspan="1" rowspan="1" align="left" valign="top">44%</td><td colspan="1" rowspan="1" align="left" valign="top">–</td><td colspan="1" rowspan="1" align="left" valign="top">46%</td><td colspan="1" rowspan="1" align="left" valign="top">50%</td><td colspan="1" rowspan="1" align="left" valign="top">–</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub>/ND (ng/ml)/(mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">263±86</td><td colspan="1" rowspan="1" align="left" valign="top">239±76</td><td colspan="1" rowspan="1" align="left" valign="top">0.092</td><td colspan="1" rowspan="1" align="left" valign="top">253±83</td><td colspan="1" rowspan="1" align="left" valign="top">243±74</td><td colspan="1" rowspan="1" align="left" valign="top">0.576</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">CV for C<sub>2</sub>/ND (%)</td><td colspan="1" rowspan="1" align="left" valign="top">33%</td><td colspan="1" rowspan="1" align="left" valign="top">32%</td><td colspan="1" rowspan="1" align="left" valign="top">–</td><td colspan="1" rowspan="1" align="left" valign="top">33%</td><td colspan="1" rowspan="1" align="left" valign="top">31%</td><td colspan="1" rowspan="1" align="left" valign="top">–</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub>/C<sub>0</sub></td><td colspan="1" rowspan="1" align="left" valign="top">5.5±2.3</td><td colspan="1" rowspan="1" align="left" valign="top">5.0±1.6</td><td colspan="1" rowspan="1" align="left" valign="top">0.270</td><td colspan="1" rowspan="1" align="left" valign="top">6.4±2.3</td><td colspan="1" rowspan="1" align="left" valign="top">6.6±2.3</td><td colspan="1" rowspan="1" align="left" valign="top">0.684</td></tr></tbody></table><table-wrap-foot><fn><p>ND, normalized CsA-ME dose; CV, coefficient of variation.</p></fn><fn id="TBLFN3"><p><sup>a</sup>Wilcoxon rank sum test.</p></fn></table-wrap-foot></table-wrap></p>
<p>There was no significant difference in pharmacokinetic parameters when patients were stratified by gender, age, presence or absence of DGF, or pre-existing diabetes.</p>
<p>Patients who discontinued steroids between month 3 and month 12 (<italic>n</italic> = 19) showed a significant increase in C<sub>2</sub>/ND ratio, while this relationship remained unchanged in those who continued to receive steroids. The significant increase in C<sub>2</sub>/C<sub>0</sub> between month 3 and month 12 was present in all patients regardless of whether steroids were continued or discontinued (<xref rid="TBL4">Table 4</xref>).
<table-wrap id="TBL4" position="float"><label><bold>Table 4.</bold></label><caption><p>Pharmacokinetic parameters in patients in whom steroids were continued or discontinued at month 12</p></caption><table><thead><tr><th colspan="1" rowspan="1" align="left" valign="top"></th><th colspan="1" rowspan="1" align="left" valign="top">Steroids at month 12 (<italic>n</italic> = 79)</th><th colspan="1" rowspan="1" align="left" valign="top">No steroids at month 12 (<italic>n</italic> = 19)</th><th colspan="1" rowspan="1" align="left" valign="top"><italic>P</italic><xref rid="TBLFN4"><sup>a</sup></xref></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>0</sub>/ND at month 12 (ng/ml)/(mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">43±21</td><td colspan="1" rowspan="1" align="left" valign="top">42±17</td><td colspan="1" rowspan="1" align="left" valign="top">n.s.</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>P</italic>-value for change in C<sub>0</sub>/ND from month 3 to month 12</td><td colspan="1" rowspan="1" align="left" valign="top"><0.001</td><td colspan="1" rowspan="1" align="left" valign="top">0.03</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub>/ND at month 12 (ng/ml)/(mg/kg)</td><td colspan="1" rowspan="1" align="left" valign="top">238±72</td><td colspan="1" rowspan="1" align="left" valign="top">286±91</td><td colspan="1" rowspan="1" align="left" valign="top">0.03</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>P</italic>-value for change in C<sub>2</sub>/ND from month 3 to month 12</td><td colspan="1" rowspan="1" align="left" valign="top">n.s.</td><td colspan="1" rowspan="1" align="left" valign="top">0.04</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C<sub>2</sub>/C<sub>0</sub> at month 12</td><td colspan="1" rowspan="1" align="left" valign="top">6.3±2.0</td><td colspan="1" rowspan="1" align="left" valign="top">7.6±3.0</td><td colspan="1" rowspan="1" align="left" valign="top">n.s.</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>P</italic>-value for change in C<sub>2</sub>/C<sub>0</sub> from month 3 to month 12</td><td colspan="1" rowspan="1" align="left" valign="top"><0.001</td><td colspan="1" rowspan="1" align="left" valign="top"><0.001</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr></tbody></table><table-wrap-foot><fn><p>All patients received steroids to month 3. ND, normalized CsA-ME dose.</p></fn><fn id="TBLFN4"><p><sup>a</sup>Wilcoxon rank sum test.</p></fn></table-wrap-foot></table-wrap></p>
<p>The inter-individual coefficient of variation was higher for C<sub>0</sub>/ND than for C<sub>2</sub>/ND at 3 months (<italic>P</italic><0.05) and at 12 months (<italic>P</italic><0.01) (<xref rid="TBL2">Table 2</xref>). In terms of intra-individual stability of the dose–blood level relationship, the change from month 3 to month 12 was −16±31% for C<sub>0</sub>/ND and +9±55% for C<sub>2</sub>/ND. Intra-individual stability was even more limited for the relationship between C<sub>2</sub> and C<sub>0</sub> (C<sub>2</sub>/C<sub>0</sub> ratio), which increased from month 3 to month 12 by 39±68%.</p>
</sec>
<sec>
<title>Discussion</title>
<p>This longitudinal analysis is the first to assess CsA pharmacokinetic parameters in both the <italic>de novo</italic> and maintenance phases for the same renal transplant patients.</p>
<p>Our results confirmed that CsA-ME bioavailability increases over the first 3 months post-transplant in a larger population than has previously been studied, and for the first time in patients receiving a third immunosuppressive agent (mostly mycophenolate mofetil). A substantial initial increase in bioavailability over the first few weeks post-transplant has previously been observed in renal transplant recipients receiving a dual regimen [<xref rid="BIB6">6</xref>,<xref rid="BIB15">15</xref>]. A Canadian study reported that CsA pharmacokinetic characteristics vary widely during the first 2 weeks post-transplant, becoming more stable and homogeneous by day 14 [<xref rid="BIB15">15</xref>]. Subsequently, a prospective international trial found that the time to maximal concentration of CsA declined from 1.94 h at day 3 to 1.52 h at day 84 post-transplant [<xref rid="BIB7">7</xref>]. Several factors may contribute to these changes, including recovery from post-operative gastroparesis, and co-medications that may influence the activity of intestinal P-glycoprotein and/or metabolizing enzymes.</p>
<p>Between months 3 and 12, the relationship between C<sub>2</sub> level and CsA-ME dose remained generally stable. Unexpectedly, however, the decrease of C<sub>0</sub> between months 3 and 12 was significantly more pronounced than the decrease in dose, such that the ratio of C<sub>0</sub> to normalized CsA-ME dose declined by 22% on average, with a corresponding increase in the C<sub>2</sub>/C<sub>0</sub> relationship. As a result, CsA exposure may be higher at month 12 than month 3 despite a similar C<sub>0</sub> value. This can be explained by an acceleration in CsA cytochrome P4503A4 complex. Cytochrome P4503A4 is thought to be the most important factor in determining the rate of CsA metabolism after the first weeks post-transplant in renal transplant patients receiving a calcineurin inhibitor [<xref rid="BIB16">16</xref>]. Recently, a significant increase in intestinal CYP3A4 clearance of CsA over time that may, in part, be due to heightened activity of the enzyme, was demonstrated in CsA-treated patients that was not apparent with sirolimus or tacrolimus [<xref rid="BIB17">17</xref>]. If CsA clearance accelerates over time to a clinically relevant extent, one would expect this to be apparent in both C<sub>2</sub>/dose and C<sub>0</sub>/dose. However, in this population of patients from the MO2ART study, we only saw this reflected in the C<sub>0</sub>/dose relationship.</p>
<p>We assessed several patient subgroups (elderly, females, patients with DGF), none of which appeared to have a distinctly different pharmacokinetic profile, although minor variations may not have been detected due to relatively low numbers in the subpopulations and interpatient variability. It has been postulated that diabetic patients have impaired CsA absorption [<xref rid="BIB18">18</xref>], but within our small population of diabetics (<italic>n</italic> = 5) this was not apparent. Patients who discontinued steroids prior to month 12 appeared to have a higher absorption at month 12 compared with those who were maintained on steroids, but the increase in elimination and metabolism between month 3 and month 12 was highly significant in both groups.</p>
<p>Finally, our results corroborate findings from a previous study in stable C<sub>0</sub>-monitored renal transplant patients which showed that more than half of patients had C<sub>2</sub> levels above the upper target level, and that CsA dose reduction in these patients led to a decrease of serum creatinine [<xref rid="BIB19">19</xref>]. Midtvedt <italic>et al.</italic> [<xref rid="BIB20">20</xref>] subsequently reported that C<sub>2</sub> monitoring of maintenance renal transplant patients may detect overexposure to CsA, specified in their study to be C<sub>2</sub> level above 700–800 ng/ml [<xref rid="BIB20">20</xref>]. Findings from the current study also indicated that the inter-patient coefficient of variation of dose-normalized C<sub>2</sub> is significantly lower than for C<sub>0</sub>, at both 3 and 12 months post-transplant.</p>
<p>To date, the changes we observed in the ratio of C<sub>0</sub> to weight-normalized dose of CsA-ME during months 3–12, which resulted in divergent patterns of C<sub>0</sub>/dose and C<sub>2</sub>/dose over time, have not been reported elsewhere. Further extended pharmacokinetic assessments are required to confirm our findings. We acknowledge the limitations of our investigation, in particular the small number of time points for which both C<sub>0</sub> and C<sub>2</sub> samples were available, which precluded calculation of area under the curve (AUC<sub>0–4</sub>) or an in-depth analysis of intra-individual variability. Neither do our dataset provide an explanation for the significant increase in C<sub>2</sub>/ND among patients who were steroid-free between months 3 to 12, while the ratio remained stable in patients receiving steroids. We can only speculate that this may have been due to investigators’ concern to maintain adequate immunosuppression in the absence of steroid therapy. However, it is interesting to note that Lemahieu <italic>et al.</italic> [<xref rid="BIB21">21</xref>] recently reported a fall in CYP3A4 and PGP activity over time post-transplant, and proposed that the most plausible explanation was the concomitant tapering of steroid dose. Lastly, while we are aware that the CsA dose was adjusted based on C<sub>2</sub> and not C<sub>0</sub>, we do not believe that this will have modified the C<sub>2</sub>/C<sub>0</sub> ratio. The strengths of the analysis are the large and homogenous patient population, followed prospectively over the first year from time of transplant, the capacity to assess subpopulations, the use of a central laboratory to standardize CsA measurements, and the precisely timed assessments of pharmacokinetic parameters under study conditions.</p>
<p>In summary, we confirmed that CsA-ME absorption increases between the first week and month 3 post-transplant. Unexpectedly, our results indicated that CsA metabolism and elimination accelerates between month 3 and month 12, which may result in progressive underestimation of CsA exposure with C<sub>0</sub> monitoring. We conclude that C<sub>2</sub> monitoring is a valuable tool and can contribute to optimal individualized CsA treatment not only in the early post-transplant phase, but also throughout the first year post-transplant.</p>
</sec>
<sec>
<title></title>
<p><italic>Conflict of interest statement</italic>. E. Cole, S. Chapman, K. Midtvedt and E. Thervet have received honoraria from Novartis for speaking at scientific meetings and received financial support for research activity. P. Keown holds research grants and contracts from Novartis, and has received honoraria from Novartis for speaking at scientific meetings. H. Prestele is an employee of Novartis Pharma AG.</p>
</sec>
</body>
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</istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases</title></titleInfo><name type="personal"><namePart type="given">Matthias</namePart><namePart type="family">Büchler</namePart><affiliation>Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steve</namePart><namePart type="family">Chadban</namePart><affiliation>Royal Prince Alfred Hospital, Sydney, Australia,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Edward</namePart><namePart type="family">Cole</namePart><affiliation>Renal Transplant Program, Toronto General Hospital, Toronto, Canada,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karsten</namePart><namePart type="family">Midtvedt</namePart><affiliation>Medical Department of Nephrology, Rikshospitalet, Oslo, Norway,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eric</namePart><namePart type="family">Thervet</namePart><affiliation>Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hans</namePart><namePart type="family">Prestele</namePart><affiliation>Novartis Pharma AG, Basel, Switzerland and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul</namePart><namePart type="family">Keown</namePart><affiliation>Department of Medicine, University of British Columbia, Vancouver, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="other" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-7474895G-0">other</genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2006-01</dateIssued><dateCreated encoding="w3cdtf">2005-10-04</dateCreated><copyrightDate encoding="w3cdtf">2006</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Background. Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. Methods. Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. Results. C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C2/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01). Conclusions. CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.</abstract><note type="author-notes">Correspondence and offprint requests to: Dr Matthias Büchler, Department of Nephrology and Clinical Immunology, C.H.U. Tours, 2 Boulevard Tonnellé 37044 Tours, France. Email: buchler@med.univ-tours.fr</note><subject lang="en"><genre>KWD</genre><topic>absorption</topic><topic>C2 monitoring</topic><topic>cyclosporine microemulsion</topic><topic>renal transplantation</topic></subject><relatedItem type="host"><titleInfo><title>Nephrology Dialysis Transplantation</title></titleInfo><titleInfo type="abbreviated"><title>Nephrol. Dial. Transplant.</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><subject><topic>Original Articles: Dialysis and Transplantation</topic></subject><identifier type="ISSN">0931-0509</identifier><identifier type="eISSN">1460-2385</identifier><identifier type="PublisherID">ndt</identifier><identifier type="PublisherID-hwp">ndt</identifier><identifier type="PublisherID-nlm-ta">Nephrol Dial Transplant</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>21</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>197</start><end>202</end></extent></part></relatedItem><identifier type="istex">5B276E4D1C60DD49B003B96C623017CA41E3D66E</identifier><identifier type="DOI">10.1093/ndt/gfi113</identifier><identifier type="local">gfi113</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 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