Influence of ABCB1 polymorphisms on Cyclosporine Pharmacokinetics and acute Graft versus Host Disease in Children undergoing Hematopoietic Stem Cell Transplantation

Diplôme Master Influence of ABCB1 polymorphisms on Cyclosporine Pharmacokinetics and acute Graft versus Host Disease in Children undergoing Hematopoietic Stem Cell Transplantation eng 2019 author Fernandez Benjamin 806165 collaborator Huezo-Diaz Patricia director Ansari Djaberi Marc Georges 61572 Introduction: Cyclosporine A (CsA), is the major immunosuppressant used to prevent graft- versus-host disease (GvHD). It is a drug with narrow therapeutic index: underdosing may lead to severe GvHD and rejection and overdosing to toxic events and relapse. Thus, therapeutic drug monitoring (TDM) is required to reach a target CsA minimal and maximal blood concentration value, chosen according to patient's characteristics and disease. Genetic variations are set to play an increasing role in inter-patient variability and efficacy of the treatment. As ABCB1 gene is known to transport many drugs including CsA, genetic variations within this gene could impact CsA pharmacokinetics (PK) and the apparition of GvHD. Aim: This literature search intends to evaluate if ABCB1 gene is worth pursuing for future GvHD association studies in CsA within the pediatric HSCT scenario and predictive models. Method: Based on PubMed and PharmGKB databases, to perform a literature review on ABCB1 variants and their role in CsA PK, efficacy and toxicity in pediatric transplantation. Results: 323 articles were identified as a result of a first research on PubMed and PharmGKB. After removing duplications (11 excluded), filtering (246 excluded) and manually browsing the remaining articles (55 excluded), a total of 5 papers were analyzed. ABCB1 1236C>T and 3435C>T single nucleotide proteins (SNPs) could induce functional variations in ABCB1 expression or activity that could impact CsA PK. For ABCB1 2677G>T/A, we found some contradictory results. Other less known alleles from ABCB1 (1199G>A, IVS49+21C>T, rs4148732, rs6950978) showed interesting association with CsA PK and/or GvHD. Haplotypes could have an impact on CsA PK, mainly by the effect of the 3435C>T allele. Conclusion: ABCB1 gene could be associated with differential exposure to CsA in pediatric transplant recipients when administered orally. As in the HSCT setting CsA is initially administered intravenously, ABCB1 would have a different impact on CsA metabolization as it would preferably modulate the immunosuppressive activity when entering the T-cells rather than modulating its plasma concentration. After the oral conversion of CsA, ABCB1 could prove to play a larger role and to be useful in adjusting doses. In addition, when examining certain variants, whether individually or in haplotype, patient characteristics (ethnicity, age etc.) are vital to take into account to understand the direction of functionality. Dewey 618 58 Département de pédiatrie, gynécologie et obstétrique 223 false 564 Oncologie et hématologie pédiatriques 907 ce0ee9d6-13c9-4289-9650-b56d84b985cd Master thesis Public Memoire_Master_Benjamin_Fernandez.pdf 6085227 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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Influence of ABCB1 polymorphisms on Cyclosporine Pharmacokinetics and acute Graft versus Host Disease in Children undergoing Hematopoietic Stem Cell Transplantation				2019	139	197

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Fernandez, Benjamin