Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2010-10-21

AUTHORS

Cécile Gérard, Nathalie Bleyzac, Pascal Girard, Gilles Freyer, Yves Bertrand, Michel Tod

ABSTRACT

ABSTRACTPurposeIn hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs.MethodsA physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30).ResultsAt steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally.ConclusionHence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C2 and C0 concentrations. More... »

PAGES

531-539

References to SciGraph publications

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  • 2003-10-01. Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors in BONE MARROW TRANSPLANTATION
  • 2004-01-12. Increased incidence of acute graft-versus-host disease with the continuous infusion of cyclosporine A compared to twice-daily infusion in BONE MARROW TRANSPLANTATION
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  • 1997-04-01. A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow Transplantation (EBMT) in BONE MARROW TRANSPLANTATION
  • 1999-09-01. Low-dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukaemia in BONE MARROW TRANSPLANTATION
  • 2006-09-18. Cyclosporine short infusion and C2 monitoring in haematopoietic stem cell transplant recipients in BONE MARROW TRANSPLANTATION
  • 2003-10-16. Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors in BONE MARROW TRANSPLANTATION
  • 1998-09-01. Low incidence of acute graft-versus-host disease and recurrent leukaemia in patients undergoing allogeneic haemopoietic stem cell transplantation from sibling donors with methotrexate and dose-monitored cyclosporin A prophylaxis in BONE MARROW TRANSPLANTATION
  • 2010-09-02. Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model in PHARMACEUTICAL RESEARCH
  • 2001-05-01. Haematopoietic cell transplantation as immunotherapy in NATURE
  • 1994-01. Adjusted-dose continuous-infusion cyclosporin A to prevent graft-versus-host disease following allogeneic bone marrow transplantation in ANNALS OF HEMATOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s11095-010-0299-z

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    http://dx.doi.org/10.1007/s11095-010-0299-z

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    https://www.ncbi.nlm.nih.gov/pubmed/20963627


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    33 schema:description ABSTRACTPurposeIn hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs.MethodsA physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30).ResultsAt steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally.ConclusionHence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C2 and C0 concentrations.
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