Precision Medicine Approaches to Immunosuppression Using Pharmacogenomics and the Microbiome

Abstract

In this thesis, I provide two examples of precision medicine applications to currently unsolved drug related problems. In chapter 1, the influence of the microbiome on the enterohepatic recirculation of mycophenolate mofetil (MMF) in hematopoietic stem cell transplant recipients (HCT) is described. There is substantial unexplained interindividual variability in MMF pharmacokinetics. This work illustrates that variability in the gut microbiome composition is associated with enterohepatic recirculation of the mycophenolic acid (MPA), the active metabolite of MMF, and consequently differences in drug exposure. In chapter 2, the influence of CYP3A4 and CYP3A5 genotypes on the magnitude of the drug-drug interaction between tacrolimus and steroids in kidney transplant recipients is described. This drug-drug interaction, while well-known, is unpredictable. Some individuals have an induction of tacrolimus clearance in the presence of steroids and others have little to no changes in clearance. This analysis shows that individuals who carry a loss of function allele such as CYP3A5*3 have a minor and clinically insignificant drug-drug interaction whereas individuals who express CYP3A5 and carry at least one CYP3A5*1 allele have a significant tacrolimus-steroid interaction which results in higher tacrolimus dose requirements during steroid use.