The Impact of Pharmacogenomic CYP3A5 Variants on Calcineurin Inhibitor Metabolism and SLCO1B1 Variants on Methotrexate in Adult Allogeneic BMT Patients

Abstract

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.