Mary Thoma, Kimberly Langer, Patricia McLean, David Dingli
{"title":"药物基因组学CYP3A5变异对钙调磷酸酶抑制剂代谢的影响以及SLCO1B1变异对成人异基因BMT患者甲氨蝶呤的影响","authors":"Mary Thoma, Kimberly Langer, Patricia McLean, David Dingli","doi":"10.1016/j.tpr.2022.100115","DOIUrl":null,"url":null,"abstract":"<div><p>Allogeneic blood and marrow transplant (BMT) is used to transplant a new immune system in patients with hematologic malignancies or immune-mediated disease. BMT patients require initial immune suppression to prevent graft rejection and graft versus host disease (GVHD). Tacrolimus and cyclosporine are calcineurin inhibitors (CNI) and methotrexate is an antimetabolite used to mitigate this immune response. Tacrolimus has data supporting oral dose variation based on pharmacogenomic (PGx) studies for Intermediate Metabolizers (IM) and Poor Metabolizers (PM) on studies done in kidney transplant patients. There are fewer studies on BMT patients in this field, and even less on the variability of IV to oral conversion dosing and first pass metabolism effect based on PGx profiles. Methotrexate has been shown to have PGx mutations affecting its metabolism at higher dosing used for chemotherapy, but its impact on BMT patient dosing is not well-defined. Based on our study, we found statistically significant variability in Tacrolimus concentration based on drug assay levels compared with dosing for Intravenous (IV) and oral formulation based on PGx predicted phenotypes. We further noted a profound effect on first pass metabolism when transitioning between IV and oral dosing of Tacrolimus based on PGx predicted phenotypes. The average oral dose in predicted IM phenotypes divided by the IV dose was 2.68. For the predicted PM phenotype, the average oral dose divided by the IV dose was 1.18. The p-value in a two-tailed nonparametric T-test with equal variance assessing the conversion factor from IV to oral dosing in predicted IM versus PM phenotypes was significant with a p-value of 0.002. Methotrexate metabolism did not seem to be affected by PGx mutations at the doses used for BMT GVHD prevention.</p></div>","PeriodicalId":37786,"journal":{"name":"Transplantation Reports","volume":"7 4","pages":"Article 100115"},"PeriodicalIF":0.0000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451959622000233/pdfft?md5=ef78481acb104ede6f97fc959fcd2315&pid=1-s2.0-S2451959622000233-main.pdf","citationCount":"0","resultStr":"{\"title\":\"The Impact of Pharmacogenomic CYP3A5 Variants on Calcineurin Inhibitor Metabolism and SLCO1B1 Variants on Methotrexate in Adult Allogeneic BMT Patients\",\"authors\":\"Mary Thoma, Kimberly Langer, Patricia McLean, David Dingli\",\"doi\":\"10.1016/j.tpr.2022.100115\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Allogeneic blood and marrow transplant (BMT) is used to transplant a new immune system in patients with hematologic malignancies or immune-mediated disease. BMT patients require initial immune suppression to prevent graft rejection and graft versus host disease (GVHD). Tacrolimus and cyclosporine are calcineurin inhibitors (CNI) and methotrexate is an antimetabolite used to mitigate this immune response. Tacrolimus has data supporting oral dose variation based on pharmacogenomic (PGx) studies for Intermediate Metabolizers (IM) and Poor Metabolizers (PM) on studies done in kidney transplant patients. There are fewer studies on BMT patients in this field, and even less on the variability of IV to oral conversion dosing and first pass metabolism effect based on PGx profiles. Methotrexate has been shown to have PGx mutations affecting its metabolism at higher dosing used for chemotherapy, but its impact on BMT patient dosing is not well-defined. Based on our study, we found statistically significant variability in Tacrolimus concentration based on drug assay levels compared with dosing for Intravenous (IV) and oral formulation based on PGx predicted phenotypes. We further noted a profound effect on first pass metabolism when transitioning between IV and oral dosing of Tacrolimus based on PGx predicted phenotypes. The average oral dose in predicted IM phenotypes divided by the IV dose was 2.68. For the predicted PM phenotype, the average oral dose divided by the IV dose was 1.18. The p-value in a two-tailed nonparametric T-test with equal variance assessing the conversion factor from IV to oral dosing in predicted IM versus PM phenotypes was significant with a p-value of 0.002. Methotrexate metabolism did not seem to be affected by PGx mutations at the doses used for BMT GVHD prevention.</p></div>\",\"PeriodicalId\":37786,\"journal\":{\"name\":\"Transplantation Reports\",\"volume\":\"7 4\",\"pages\":\"Article 100115\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2451959622000233/pdfft?md5=ef78481acb104ede6f97fc959fcd2315&pid=1-s2.0-S2451959622000233-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Transplantation Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2451959622000233\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Transplantation Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2451959622000233","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Medicine","Score":null,"Total":0}
The Impact of Pharmacogenomic CYP3A5 Variants on Calcineurin Inhibitor Metabolism and SLCO1B1 Variants on Methotrexate in Adult Allogeneic BMT Patients
Allogeneic blood and marrow transplant (BMT) is used to transplant a new immune system in patients with hematologic malignancies or immune-mediated disease. BMT patients require initial immune suppression to prevent graft rejection and graft versus host disease (GVHD). Tacrolimus and cyclosporine are calcineurin inhibitors (CNI) and methotrexate is an antimetabolite used to mitigate this immune response. Tacrolimus has data supporting oral dose variation based on pharmacogenomic (PGx) studies for Intermediate Metabolizers (IM) and Poor Metabolizers (PM) on studies done in kidney transplant patients. There are fewer studies on BMT patients in this field, and even less on the variability of IV to oral conversion dosing and first pass metabolism effect based on PGx profiles. Methotrexate has been shown to have PGx mutations affecting its metabolism at higher dosing used for chemotherapy, but its impact on BMT patient dosing is not well-defined. Based on our study, we found statistically significant variability in Tacrolimus concentration based on drug assay levels compared with dosing for Intravenous (IV) and oral formulation based on PGx predicted phenotypes. We further noted a profound effect on first pass metabolism when transitioning between IV and oral dosing of Tacrolimus based on PGx predicted phenotypes. The average oral dose in predicted IM phenotypes divided by the IV dose was 2.68. For the predicted PM phenotype, the average oral dose divided by the IV dose was 1.18. The p-value in a two-tailed nonparametric T-test with equal variance assessing the conversion factor from IV to oral dosing in predicted IM versus PM phenotypes was significant with a p-value of 0.002. Methotrexate metabolism did not seem to be affected by PGx mutations at the doses used for BMT GVHD prevention.
期刊介绍:
To provide to national and regional audiences experiences unique to them or confirming of broader concepts originating in large controlled trials. All aspects of organ, tissue and cell transplantation clinically and experimentally. Transplantation Reports will provide in-depth representation of emerging preclinical, impactful and clinical experiences. -Original basic or clinical science articles that represent initial limited experiences as preliminary reports. -Clinical trials of therapies previously well documented in large trials but now tested in limited, special, ethnic or clinically unique patient populations. -Case studies that confirm prior reports but have occurred in patients displaying unique clinical characteristics such as ethnicities or rarely associated co-morbidities. Transplantation Reports offers these benefits: -Fast and fair peer review -Rapid, article-based publication -Unrivalled visibility and exposure for your research -Immediate, free and permanent access to your paper on Science Direct -Immediately citable using the article DOI