Impact of CYP3A5 Status on the Clinical and Financial Outcomes Among African American Kidney Transplant Recipients

Abstract

Background. Pharmacogenetic profiling of transplant recipients demonstrates that the marked variation in the metabolism of immunosuppressive medications, particularly tacrolimus, is related to genetic variants. Patients of African ancestry are less likely to carry loss-of-function (LoF) variants in the CYP3A5 gene and therefore retain a rapid metabolism phenotype and higher clearance of tacrolimus. Patients with this rapid metabolism typically require higher dosing to achieve therapeutic trough concentrations. This study aims to further characterize the impact of CYP3A5 genotype on clinical outcomes and financial expenditure. Methods. The CYP3A5 phenotype status was identified in 438 adult kidney transplant (KTx) recipients (96% were African American) using 3 LoF alleles ( CYP3A5*3 , *6 or *7 ). Individuals were categorized as rapid metabolism phenotype without LoF alleles‚ intermediate phenotype for 1 LoF allele‚ and slow phenotype for 2 LoF alleles. KTx outcomes (patient/kidney survival and Medicare spending) were determined using linked transplant registry and claims data. Results. Among the cohort, 23% had a rapid, 47% intermediate, and 30% a slow metabolism phenotype based on genotype. At 3 y, the rate of death censored graft failure and all cause graft failure was highest in the rapid metabolism phenotype and lowest in the intermediate metabolism phenotype group. First-year Medicare reimbursement differed significantly by genotype (rapid: $79 535, intermediate: $72 796, slow: $79 346, P = 0.03). After adjustment for donor and recipient characteristics, care for patients with intermediate metabolism was $4790 less expensive ( P = 0.003). Conclusions. Pharmacogenomic assessment of African American KTx recipients may be useful to guide therapy when as CYP3A5 functional variants appear to be associated with differential outcome and spending after transplant.

Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers

“…As the number of troughs measured and dose changes made increases, resource utilization from laboratory, phlebotomy, pharmacy, and nursing may be increased in an already resource limited setting. We did not evaluate the cost of these resources, but in a recent study, total first year Medicare reimbursement differed by CYP3A5 phenotype where EM had greater spending (p = 0.003) compared to IM 28 . A recent study showed that de novo DSA development was more likely to occur in CYP3A5 expressors (EM or IMs) than nonexpressors (PM) (19% vs. 10%, p = .02) and that expressors experienced more antibody mediated rejection and lower survival rates than non‐expressors 29 .…”

Assessing the Utility of a Genotype‐Guided Tacrolimus Equation in African American Kidney Transplant Recipients: A Single Institution Retrospective Study

“…It has been shown that this range of genetic profiles among AA patients contributes to the higher incidence of acute rejection and reduced allograft survival observed in AA KTx recipients. 10,[17][18][19][20] Given the disproportionate potential for harm among AA transplant recipients, the Deterioration of Kidney Allograft Function (DeKAF) genomics study group developed a genotype-guided tacrolimus dosing equation specifically geared toward the genotypes prevalent among AAs. 21 With the narrow therapeutic window (initial trough goal 8-12 ng/mL) and the known variability in tacrolimus metabolism, an effective model that predicts tacrolimus clearance and dose would allow clinicians to achieve therapeutic tacrolimus troughs in less time and with fewer dose adjustments.…”

“…As a result, AA KTx recipients have a broader range of potential alleles and subsequently high variability in metabolism phenotypes. It has been shown that this range of genetic profiles among AA patients contributes to the higher incidence of acute rejection and reduced allograft survival observed in AA KTx recipients 10,17–20 …”