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Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes
Author(s) -
Bartlett Felicia E.,
Carthon Clarice E.,
Hagopian Jennifer C.,
Horwedel Timothy A.,
January Spenser E.,
Malone Andrew
Publication year - 2019
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.2300
Subject(s) - tacrolimus , medicine , population , urology , log rank test , transplantation , survival analysis , environmental health
Introduction One factor impacting tacrolimus interpatient variability is the presence of CYP 3A5 polymorphisms. Low tacrolimus concentration‐to‐dose ratios ( CDR s), or rapid metabolizers ( RM s), have been associated with poor graft function outcomes and higher biopsy‐proven acute rejection ( BPAR ) rates in a predominantly white population. Pretransplant CYP genotyping is not routinely conducted, and therefore only a small number of studies have assessed the use of tacrolimus CDR s as a surrogate for metabolism. We explored differences in outcomes between patients with low tacrolimus CDR s and high tacrolimus CDR s (i.e., nonrapid metabolizers [ NRM s]) in a diverse patient population. Objective To determine the relationship between tacrolimus CDR s and graft and patient outcomes in kidney transplant recipients at a large transplant center between 2006 and 2016. Methods Inclusion criteria consisted of adult kidney transplant recipients who received rabbit antithymocyte globulin induction followed by a maintenance regimen of tacrolimus, mycophenolate, and prednisone. The primary end point was BPAR at 1 year. Secondary end points included graft survival, patient survival, and toxicities. Determination of clusters was conducted using the two‐step cluster analysis with a defined two‐cluster distribution. Kaplan‐Meier survival curves were created using the log‐rank test. Results The NRM cluster consisted of 322 patients with a mean CDR of 2.91 ng/ml/mg. The RM cluster consisted of 932 patients with a mean CDR of 1.14 ng/ml/mg. The BPAR at 1 year posttransplant was 3.7% in the NRM cluster and 3.6% in the RM cluster (p=0.95). Death at 5 years was higher in the NRM group compared with the RM group for unknown reasons (p=0.03). Differences in the incidence of posttransplant toxicities were not statistically significant at any time point, except for increased rates of cutaneous cancer at 5 years and cardiovascular disease overall in the NRM group. Conclusion Tailoring tacrolimus therapy early posttransplant based on CDR is not supported by the findings in this study.