Pharmacogenomics with a Prospective Trial Looking at How Pharmacogenomic Assessment Might Impact Blood and Marrow Transplant Patients
2023-10
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Pharmacogenomics with a Prospective Trial Looking at How Pharmacogenomic Assessment Might Impact Blood and Marrow Transplant Patients
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2023-10
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Pharmacogenomics (PGx) is an evolving branch of medicine in Individualized Medicine that assesses potential response to medications by correlating these with a person’s genetic profile. PGx studies assess genes responsible for the coding of the proteins associated with drug metabolism. These studies link predicted phenotypes to the patient-specific haplotypes. There are databases housing the information nationally and internationally, and companies providing resources to assess PGx profiles for people and give recommendations for actions on these. There are obstacles, however, preventing widespread adoption of this science into mainstream medicine. We recognize the potential of the data to impact patient care but have yet to implement the systems needed to accrue and analyze data on a broad population scale to identify the many genetic factors involved. We recognize many interindividual differences but have yet to fully recognize the interplay of factors including ethnic variables, histone modification, and associated mutations that can offset specific PGx mutations. We lack a universally functional patient electronic medical record that can interface with databases accruing PGx data to provide reliable and translatable data for providers and patients. Assessing PGx patient profiles is now relatively fast and inexpensive, but still lacks the wide-spread applicability in medical practice that it could have. This thesis will initially review the current state of PGx research. It looks at some of the methods and design approaches to PGx research. It then will delve into how this research is assimilated, stored, and made accessible to the companies and providers using this today. It will discuss some of the limitations influencing predictive outcomes in the research being done. This thesis then looks at a particular subset of patients; Blood and Marrow Transplant (BMT) patients. These patients are at high risk for having a deleterious outcome from medication reactions, as they are started on multiple medications at a single point in time. This thesis will review possible PGx pathways that would lend to mutational targets for assessment in these patients. This thesis discusses data that suggests metabolizer subtypes that may occur with these mutations. This thesis also discusses how subtherapeutic or supratherapeutic drug levels can occur at standard dosing based on mutations in enzymatic pathways. It explores the literature linking these PGx targets to drugs used in transplant. This will lead into why we included the PGx targets in the prospective trial we undertook for BMT patients. We present the results of a prospective trial we conducted. We obtained PGx data on 50 BMT patients and assessed this for mutational influence on drug metabolism. We present data that we published on the impact of PGx mutations and metabolism of Tacrolimus and cyclosporine by comparing dosing and assessment of drug levels in these patients in the first 100 days after transplant. We assessed possible deleterious effects of Methotrexate by assessing whether patients were able to complete their prescribed course of this drug, without side effects which can limit the use of this medication. We found no statistically significant link to mutational variants and Methotrexate side effect. We discuss these results in more detail. We also discuss further targets that, based on prior PGx studies, were thought to possibly impact the metabolism of medications used in BMT patients. We included these in our original study design, but not in the published results. One mutational target was thought to influence metabolism of Voriconazole and proton pump inhibitors. Two others were thought to influence narcotics or opioids. The results of analysis of these targets were not statistically significant, and we assess and discuss this in detail. We then conclude the analysis of our study results by including a case report with a specific patient impact assessment. This exemplifies why this PGx research is critically needed in real time to help get patients the right drugs at the right doses to meet their needs. It shows how possible PGx variables can contribute to a cascade of deleterious events, even if they aren’t shown to be the inciting event leading to a crisis. We then conclude with a synopsis of the thesis. We include a brief discussion of the research and potential for future directions.
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University of Minnesota Ph.D. dissertation. October 2023. Major: Biomedical Informatics and Computational Biology. Advisors: David Dingli, Chad Myers. 1 computer file (PDF); viii, 68 pages.
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Thoma, Mary. (2023). Pharmacogenomics with a Prospective Trial Looking at How Pharmacogenomic Assessment Might Impact Blood and Marrow Transplant Patients. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/260677.
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