Personalizing Therapy In Transplantation: Focus On Pharmacokinetics, Pharmacodynamics And Pharmacogenomics Of Drugs Used In Hematopoeitic Stem Cell And Kidney Transplant

Abstract

Patients treated with a standardized dosing strategy often demonstrate a substantial variability in drug response. Number of factors influences systemic exposure of the drug and its effect on the biological targets. The central objective of this thesis was to identify biomarkers and develop personalized dosing of drugs used in hematopoietic stem cell transplant (HSCT) and kidney transplant to improve outcomes. Fludarabine is a chemotherapeutic drug used in reduced intensity conditioning (RIC) HSCT. High fludarabine exposure is associated with greater treatment related mortality (TRM). Fludarabine dose reductions are commonly empirical for obese and/or those with renal dysfunction. We developed a dosing equation, accounting for creatinine clearance and body size. Using this model to make dose reductions will reduce the probability of fludarabine overexposure and reduce TRM. Cyclophosphamide (Cy) is another chemotherapeutic agent used in RIC HSCT, associated with high toxicity and TRM. Due to complex metabolic pathway it is unclear which metabolite is most important to predict Cy’s efficacy and toxicity. We evaluated the association between the active metabolite, phosphoramide mustard (PM), exposure and TRM. We found that higher PM AUC of was associated with greater TRM. We further identified creatinine clearance and gender to influence PM clearance and volume of distribution respectively. Tacrolimus is an immunosuppressant used in kidney transplant recipients. African Americans show very high variability in tacrolimus exposure and poor outcomes. We developed a tacrolimus dosing model, taking into account the clinical and genetic variants to individualize dose in African Americans that could help achieve the target concentrations quicker and improve outcomes. Mycophenolic acid (MPA) is another immunosuppressant used in kidney transplant recipients. Enterohepatic recycling and high variability in trough concentrations make it very difficult to use MPA concentrations for routine therapeutic monitoring. We conducted an RNA sequencing analysis to measure gene expression to identify novel biomarkers to predict MPA efficacy and toxicity. We identified transient changes in gene expression post MPA administration and that expression of 3 genes out of ~20000 were significantly associated with MPA trough concentrations. Additional studies are required to identify if transient changes in gene expression are associated with MPA related outcomes.