Prevalence of CYP3A5 Genomic Variances and Their Impact on Tacrolimus Dosing Requirements among Kidney Transplant Recipients in Eastern North Carolina

Abstract

Study Objective

To assess the prevalence of CYP3A5 genomic variances and their impact on tacrolimus dosing requirements among kidney transplant recipients in eastern North Carolina.

Design

Single-center, retrospective cohort study.

Setting

Large tertiary care medical center.

Patients

A total of 162 adults who received a kidney transplant between March 1, 2013, and February 28, 2015, and received oral tacrolimus as part of their maintenance immunosuppression; of these patients, 85 patients expressed a genotype with a CYP3A5*1 variant (CYP3A5*1 group), and 77 patients expressed genotypes with other CYP3A5 variants (nonexpressor group).

Measurements And Main Results

All patients were followed for 1 year posttransplantation. The primary endpoint was the tacrolimus total daily dose (TDD) required to achieve the first therapeutic trough level based on the presence or absence of the CYP3A5*1 variant. The prevalence of different CYP3A5 variants across race-ethnicities in the study cohort was determined by CYP3A5 genotyping for each patient. The CYP3A5*1 and nonexpressor groups did not differ significantly with respect to sex, mean age, or mean weight. The CYP3A5*1 group was largely African-American (93%, p<0.0005) compared with other race-ethnicities. Among the CYP3A5*1 expressors compared with nonexpressors, the mean tacrolimus TDD in milligrams at the first therapeutic tacrolimus level was significantly higher (12 vs 8 mg/day, p≤0.001). Similarly, the mean tacrolimus TDD in milligrams/kilogram was 50% greater among CYP3A5*1 expressors (0.15 vs. 0.1 mg/kg/day, p≤0.0005). The predominant genotypic variants were CYP3A5*3/*3 (33%), CYP3A5*1/*3 (20%), and CYP3A5*1/*1 (19%).

Conclusion

This study illustrates the prevalence of the CYP3A5*1 variant among African-American kidney transplant recipients and the effect of this gene expression on the tacrolimus TDD. Patients with the CYP3A5*1 variant require higher tacrolimus doses, on average, to achieve desirable drug levels. In addition, this study provides transplant clinicians with insight and support to dose tacrolimus more aggressively in African-American kidney transplant recipients who may be at higher risk for both toxicities as well as poor clinical outcomes related to inadequate immunosuppression.

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