Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model
- 200 Downloads
Cyclosporin is administered by intermittent infusions (II) or continuous infusions (CI) to prevent acute graft-versus-host disease (aGVHD). Because cyclosporin disposition is nonlinear, organ exposure may be higher after II than after CI, but saturation of receptors must be accounted for. The aim of the study was to compare both types of administration using a mechanistic model.
A physiologically based pharmacokinetic model was developed to estimate cyclosporin exposure and receptor occupancies (RO) in aGVHD target organs and kidneys and to compare these estimations in pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30).
Simulations showed that the exposure to cyclosporin in the interstitial fluid of aGVHD target organs was greater at day 1 after II than after CI. In kidneys, the opposite order was observed. AUCRO in all organs was greater after CI than after II. The therapeutic index (the ratio of AUCRO in blood to AUCRO in kidneys) was greater with CI than with II.
CI may be slightly more favorable than II for aGVHD prevention.
KEY WORDScyclosporin GVHD hematopoietic stem cell transplantation PBPK modelling
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
- 5.Martin P, Bleyzac N, Souillet G, Galambrun C, Bertrand Y, Maire PH, et al. 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. Bone Marrow Transplant. 2003;32:777–84.CrossRefPubMedGoogle Scholar
- 6.Martin P, Bleyzac N, Souillet G, Galambrun C, Bertrand Y, Maire PH, et al. Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors. Bone Marrow Transplant. 2003;32:881–7.CrossRefPubMedGoogle Scholar
- 8.Przepiorka D, Shapiro S, Schwinghammer TL, Bloom EJ, Rosenfeld CS, Shadduck RK, et al. Cyclosporine and methylprednisolone after allogeneic marrow transplantation: association between low cyclosporine concentration and risk of acute graft-versus-host disease. Bone Marrow Transplant. 1991;7:461–5.PubMedGoogle Scholar
- 11.Punnett A, Sung L, Price V, Das P, Diezi M, Doyle J, et al. Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis. Ther Drug Monit. 2007;29:750–7.CrossRefPubMedGoogle Scholar
- 12.Byrne JL, Stainer C, Hyde H, Miflin G, Haynes AP, Bessell EM, et al. 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. Bone Marrow Transplant. 1998;22:541–5.CrossRefPubMedGoogle Scholar
- 13.Carlens S, Aschan J, Remberger M, Dilber M, Ringden O. 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. Bone Marrow Transplant. 1999;24:629–35.CrossRefPubMedGoogle Scholar
- 14.Ruutu T, Niederwieser D, Gratwohl A, Apperley JF. A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party of the EBMT. Bone Marrow Transplant. 1997;19:759–64.CrossRefPubMedGoogle Scholar
- 20.Kawai R, Lemaire M. Role of blood cell uptake on cyclosporin pharmacokinetics. In: Tillement P, Eckert H, editors. Proceeding of the International Symosium on Blood Binding and Drug Transfer. Paris: EFC; 1993. p. 89–108.Google Scholar
- 22.Niederberger W, Lemaire M, Maurer G, Nussbaumer K, Wagner O. Distribution and binding of cyclosporin in blood and tissues. Transplant Proc. 1983;15:2419–21.Google Scholar
- 26.D’Argenio D, Schumitzky A. ADAPT II User’s guide. Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Ressource; 1997.Google Scholar
- 31.National Cholesterol Education Program (NCEP). highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89:495–501.Google Scholar
- 38.Barama A, Perner F, Beauregard-Zollinger L. Absorption profiling of cyclosporine therapy for de novo kidney transplantation: a retrospective randomized study comparing sparse sampling to trough monitoring [abstract no. 190]. Transplantation. 2000;69(Suppl):S162.Google Scholar
- 40.Lanino E, Rondelli R, Locatelli F, Messina C, Pession A, Balduzzi A, et al. Early (day -7) versus conventional (day -1) inception of cyclosporine-A for graft-versus-host disease prophylaxis after unrelated donor hematopoietic stem cell transplantation in children. Long-term results of an AIEOP prospective, randomized study. Biol Blood Marrow Transplant. 2009;15:741–8.CrossRefPubMedGoogle Scholar