Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study.

2.50
Hdl Handle:
http://hdl.handle.net/10143/85794
Title:
Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study.
Authors:
Bremer, Sara; Vethe, Nils T; Rootwelt, Helge; Jørgensen, Pål F; Stenstrøm, Jean; Holdaas, Hallvard; Midtvedt, Karsten; Bergan, Stein
Citation:
Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. 2009, 7:64notJ Transl Med
Additional Links:
http://www.biomedcentral.com/registration/

Full metadata record

DC FieldValue Language
dc.contributor.authorBremer, Saraen
dc.contributor.authorVethe, Nils Ten
dc.contributor.authorRootwelt, Helgeen
dc.contributor.authorJørgensen, Pål Fen
dc.contributor.authorStenstrøm, Jeanen
dc.contributor.authorHoldaas, Hallvarden
dc.contributor.authorMidtvedt, Karstenen
dc.contributor.authorBergan, Steinen
dc.date.accessioned2009-11-10T13:23:57Z-
dc.date.available2009-11-10T13:23:57Z-
dc.date.issued2009-
dc.identifier.citationMycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. 2009, 7:64notJ Transl Meden
dc.identifier.issn1479-5876-
dc.identifier.pmid19635156-
dc.identifier.doi10.1186/1479-5876-7-64-
dc.identifier.urihttp://hdl.handle.net/10143/85794-
dc.description.abstractBACKGROUND: Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2nd generation CTLA4-Ig) or cyclosporine (CsA). METHODS: Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two IMPDH isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry. RESULTS: The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC0-9 h and C0) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for IMPDH1 expression, starting at week 1. Higher MPA exposure was associated with larger elevations of IMPDH1 (r = 0.81, P = 0.023, n = 7 for MPA and IMPDH1 AUC0-9 h at week 1). The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression. No difference was observed in T cell subsets between treatment groups. CONCLUSION: The significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.en
dc.language.isoenen
dc.relation.urlhttp://www.biomedcentral.com/registration/en
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Nefrologi, urologi: 772en
dc.subject.meshAdrenal Cortex Hormonesen
dc.subject.meshAgeden
dc.subject.meshAntibodies, Monoclonalen
dc.subject.meshArea Under Curveen
dc.subject.meshCD4-Positive T-Lymphocytesen
dc.subject.meshCyclosporineen
dc.subject.meshDose-Response Relationship, Drugen
dc.subject.meshDrug Therapy, Combinationen
dc.subject.meshFemaleen
dc.subject.meshFollow-Up Studiesen
dc.subject.meshHumansen
dc.subject.meshIMP Dehydrogenaseen
dc.subject.meshImmunoconjugatesen
dc.subject.meshImmunosuppressive Agentsen
dc.subject.meshInfusions, Intravenousen
dc.subject.meshKidney Transplantationen
dc.subject.meshMaleen
dc.subject.meshMetabolic Clearance Rateen
dc.subject.meshMethylprednisoloneen
dc.subject.meshMycophenolic Aciden
dc.subject.meshPilot Projectsen
dc.subject.meshPrednisoloneen
dc.subject.meshProtein Isoformsen
dc.subject.meshRecombinant Fusion Proteinsen
dc.subject.meshTime Factorsen
dc.subject.meshTransplantation, Homologousen
dc.titleMycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study.en
dc.typeJournal articleen
dc.typepeer revieweden
dc.contributor.departmentDepartment of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway. sara.bremer@rikshospitalet.noen
dc.identifier.journalJournal of translational medicineen
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