The use of pharmacokinetic models in paediatric onco-haematology: effects on clinical outcome through the examples of busulfan and cyclosporine.
Overall survival after allogeneic haematopoietic stem cell transplantation (HSCT) is reduced by the high rate of transplantation-related mortality (TRM), especially because of liver veno-occlusive disease (VOD) or acute graft-vs.-host disease (GVHD) because of the toxicity or inefficacy of busulfan and cyclosporine (CsA), respectively. Results of clinical outcome of previous studies performed to optimize busulfan and CsA therapy by controlling their pharmacokinetic variability by means of maximum a posteriori (MAP) Bayesian individualization of both drugs are presented. The 90-day VOD-free survival was significantly higher in patients with individualized busulfan doses: 97% vs. 76%. Monitoring CsA trough blood concentrations allowed us to obtain a successful GVHD outcome (mild or moderate GVHD and graft vs. leukaemia effect (GVL) in malignant diseases and no GVHD (in non-malignant ones) in the majority of our patients. Severe GVHD occurred in <5% of patients. TRM in children can be significantly decreased by using population pharmacokinetic models and MAP Bayesian individualization of dose regimens for drugs such as CsA and busulfan.
Bleyzac
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Institut d'Hématologie et d'Oncologie Pédiatrique, 1 Place Joseph Renaut, 69 008 Lyon, France. nathalie.bleyzac@chu-lyon.fr
D001499:Bayes Theorem; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D003198:Computer Simulation; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008954:Models, Biological; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D016572:Cyclosporine; D002066:Busulfan