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INTRODUCTION

LEARNING OBJECTIVES

  1. Discuss the clinical considerations of pharmacogenomics in solid organ and hematopoietic stem cell transplantation.

  2. Describe general mechanisms of action, pharmacokinetics/pharmacodynamics, adverse drug reactions, and drug interactions of transplant immunosuppressant agents.

  3. Identify gene targets that influence pharmacokinetic or pharmacodynamic phenotypes of transplant immunosuppressant agents.

  4. Given a case with pharmacogenetic testing results, provide recommendations regarding selection, dosing, monitoring, and other considerations for transplant immunosuppressant agents.

Immunosuppression is an essential component of therapy to prevent and treat allograft rejection in transplant patients.1 Many commonly prescribed post-transplant immunosuppressive agents have narrow therapeutic indexes, requiring a balance to maintain efficacy and avoid toxicity. These agents carry a risk for transplant/allograft rejection if a patient does not have adequate immunosuppression. Additionally, there are risks for complications from immunosuppression such as opportunistic infections, as well as adverse effects associated with these agents. Given that these immunosuppressive agents are associated with significant adverse effects, drug interactions, and variation in drug metabolism, it makes sense to study pharmacogenetic variation in metabolism of and response to these agents. This chapter focuses primarily on pharmacogenomics of immunosuppressive agents.

Pharmacogenomics in the transplantation domain is complex. Genetic polymorphisms may lead to variation in both response to drugs and response to transplantation. Tissue antigenicity needs to be considered, and genetic differences in human leukocyte antigen (HLA) typing, cytokines, chemokines, and restrictive allograft syndrome (RAS) may be related to risk of rejection.2 Organ failure syndromes and cancers leading to transplant and complications of infection are also of significant concern in this patient population and are covered in other chapters.

Transplant pharmacogenomics research is ongoing, and clinically actionable recommendations are still emerging for many drugs in the field. Published evidence-based clinical guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) are available for tacrolimus. Although genotype-based guidelines are not currently available for other immunosuppressive agents, there are published studies for drug–gene pairs in the transplantation literature that describe genetic polymorphisms associated with altered pharmacokinetics and pharmacodynamics for cyclosporine, mycophenolate, sirolimus, and everolimus.1,3 Azathioprine, which is no longer a common component of maintenance immunosuppression regimens following solid organ transplantation, is discussed in Chapter 7.

CALCINEURIN INHIBITORS

Calcineurin inhibitors (CNIs) have become the mainstay in immunosuppression regimens given to patients following solid organ transplantation, usually administered in combination with an antiproliferative and a glucocorticoid. Two significant CNIs are cyclosporine and tacrolimus. Cyclosporine was approved by the Food and Drug Administration (FDA) in 1983. At that time, it offered the most effective therapy to prevent allograft rejection and represented a major advancement in improving survival prospects for transplant recipients. Tacrolimus was approved by the FDA in 1994 and is currently one of the most commonly prescribed immunosuppressive agents in the setting of solid organ transplantation. Both CNIs are used as antirejection medications in kidney, liver, heart, and lung transplant, as well as for treatment of graft-versus-host disease ...

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