caa a22 4500 445312920 CHVBK 20180317142636.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s11095-010-0299-z doi (NATIONALLICENCE)springer-10.1007/s11095-010-0299-z Links Between Cyclosporin Exposure in Tissues and Graft- Versus -Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model [Elektronische Daten] [Cécile Gérard, Nathalie Bleyzac, Pascal Girard, Gilles Freyer, Yves Bertrand, Michel Tod] ABSTRACT: Purpose: In 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. Methods: A 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). Results: At steady state (1day 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. Conclusion: Hence, 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. Springer Science+Business Media, LLC, 2010 bone marrow transplantation nationallicence cyclosporin nationallicence GVHD nationallicence PBPK modelling nationallicence Gérard Cécile Université de Lyon, 69003, Lyon, France aut Bleyzac Nathalie Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France aut Girard Pascal Université de Lyon, 69003, Lyon, France aut Freyer Gilles Université de Lyon, 69003, Lyon, France aut Bertrand Yves Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France aut Tod Michel Université de Lyon, 69003, Lyon, France aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 531-539 0724-8741 28:3<531 2011 28 11095 https://doi.org/10.1007/s11095-010-0299-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0299-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gérard Cécile Université de Lyon, 69003, Lyon, France aut NATIONALLICENCE 700 1- Bleyzac Nathalie Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France aut NATIONALLICENCE 700 1- Girard Pascal Université de Lyon, 69003, Lyon, France aut NATIONALLICENCE 700 1- Freyer Gilles Université de Lyon, 69003, Lyon, France aut NATIONALLICENCE 700 1- Bertrand Yves Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France aut NATIONALLICENCE 700 1- Tod Michel Université de Lyon, 69003, Lyon, France aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 531-539 0724-8741 28:3<531 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer