A Prospective, Double-Blinded, Observational Clinical Cohort Study of the Association Between Tacrolimus Exposure and CYP3A4, CYP3A5 Genotypes in Adult Hematopoietic Stem Cell Transplant Recipients

Background

Tacrolimus has become a mainstay in the prevention and treatment of graft versus host disease (GVHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus has high potential for toxicity and requires therapeutic drug monitoring due to its narrow therapeutic drug index, with noted inter-subject variability. The hepatic cytochrome P450 pathway metabolizes the immunosuppressant, with recent studies revealing the influence of selected single-nucleotide polymorphisms (SNPs) in CYP3A4 and CYP3A5 genotypes that may influence tacrolimus pharmacokinetics (PK) and outcomes. To our knowledge, the influence of CYP3A4 and CYP3A5 genotypes on tacrolimus pharmacokinetics and pharmacodynamics (PD) has not been thoroughly studied in allo-HSCT population.  

Objectives

The primary objectives of the study are to 1) determine the effects of CYP3A4*22 and CYP3A5*1 genotypes on the pharmacokinetics of tacrolimus in allo-HSCT patients; 2) develop a comprehensive model for optimal tacrolimus starting doses in patients receiving allogeneic HSCT and monitoring for continued therapy. 

Study Design

A prospective, double-blinded cohort study is currently accruing patients in the adult allo-HSCT setting at The Ohio State University Comprehensive Cancer Center. Inclusion criteria: First time allo-HSCT from related or unrelated donors matched for 10/10 or 9/10 human leukocyte antigen (HLA)-A, -B, -C, -DRB1, and - DQB1 alleles receiving tacrolimus, > 18 years of age, and no prior tacrolimus exposure. The status of CYP3A4*22, CYP3A5*1 and CYP3A5*3 genotypes is determined prior to transplant. Serial blood samples are collected to characterize the PK for first and steady state tacrolimus doses. A validated liquid chromatography-mass spectrometry (LC/MS) assay is used to measure tacrolimus and selected metabolites level. The study is approved by the Institutional Review Board (IRB) and enrollment began in June 2012.

Results

The study has accrued 33 subjects to date. Preliminary pharmacogenetic-pharmacokinetic interim data as well as parent drug and CP3A4/5-mediated metabolites PK will be presented.

Acknowledgment

Support from NIGMS U01 GM092655 (PI: Wolfgang Sadee)