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

To assess the prevalence of CYP3A5 genomic variances and their impact on tacrolimus (TAC) dosing requirements among kidney transplant recipients in eastern North Carolina, we conducted a single‐center retrospective cohort study at a large tertiary care medical center. A total of 162 adults who received a kidney transplant between March 1, 2013, and February 28, 2015, and received oral TAC as part of their maintenance immunosuppression were enrolled. 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). All patients were followed for 1 year posttransplantation. The primary end point was the TAC 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 TAC TDD in milligrams at the first therapeutic TAC level was significantly higher (12 vs 8 mg/day, p≤0.001). Similarly, the mean TAC 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%). 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 TAC TDD. Patients with the CYP3A5*1 variant require higher TAC doses, on average, to achieve desirable drug levels. In addition, this study provides transplant clinicians with insight and support to dose TAC 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.

[1]  Min Chang Kim,et al.  Monitoring the Intracellular Tacrolimus Concentration in Kidney Transplant Recipients with Stable Graft Function , 2016, PloS one.

[2]  W. Guan,et al.  Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  W. Guan,et al.  Genotype-guided tacrolimus dosing in African American kidney transplant recipients , 2015, The Pharmacogenomics Journal.

[4]  Julia M. Barbarino,et al.  Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing , 2015, Clinical pharmacology and therapeutics.

[5]  M. Gebregziabher,et al.  African‐American Race Modifies the Influence of Tacrolimus Concentrations on Acute Rejection and Toxicity in Kidney Transplant Recipients , 2015, Pharmacotherapy.

[6]  K. Birdwell.  Role of pharmacogenomics in dialysis and transplantation , 2014, Current opinion in nephrology and hypertension.

[7]  J. Cooper,et al.  The risk of acute rejection and the influence of induction agents in lower‐risk African American kidney transplant recipients receiving modern immunosuppression , 2014, Clinical transplantation.

[8]  F. Durand,et al.  Determination of the Most Influential Sources of Variability in Tacrolimus Trough Blood Concentrations in Adult Liver Transplant Recipients: A Bottom-Up Approach , 2014, The AAPS Journal.

[9]  L. Domański,et al.  CYP3A5 and CYP3A4, but not ABCB1 polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipients. , 2014, Pharmacogenomics.

[10]  W. Weimar,et al.  ATP-binding cassette transporters as pharmacogenetic biomarkers for kidney transplantation. , 2012, Clinica chimica acta; international journal of clinical chemistry.

[11]  A. Israni,et al.  Novel Polymorphisms Associated With Tacrolimus Trough Concentrations: Results From a Multicenter Kidney Transplant Consortium , 2011, Transplantation.

[12]  D. Hricik,et al.  Influence of African-American ethnicity on acute rejection after early steroid withdrawal in primary kidney transplant recipients. , 2010, Transplantation proceedings.

[13]  M. Loriot,et al.  Optimization of Initial Tacrolimus Dose Using Pharmacogenetic Testing , 2010, Clinical pharmacology and therapeutics.

[14]  C. Staatz,et al.  Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part II , 2010, Clinical pharmacokinetics.

[15]  G. Malat,et al.  African American Kidney Transplantation Survival , 2009, Drugs.

[16]  B. Charpentier,et al.  Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. , 2008, Basic & clinical pharmacology & toxicology.

[17]  L Zhang,et al.  The Role of Ethnicity in Variability in Response to Drugs: Focus on Clinical Pharmacology Studies , 2008, Clinical pharmacology and therapeutics.

[18]  D. Brennan,et al.  The role of tacrolimus in renal transplantation , 2008, Expert opinion on pharmacotherapy.

[19]  U. Kunzendorf,et al.  CYP3A5 Genotype Markedly Influences the Pharmacokinetics of Tacrolimus and Sirolimus in Kidney Transplant Recipients , 2007, Clinical pharmacology and therapeutics.

[20]  J. Fishman,et al.  Disparities in Solid Organ Transplantation for Ethnic Minorities: Facts and Solutions , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[21]  R. Kim,et al.  Genetic variability in CYP3A5 and its possible consequences. , 2004, Pharmacogenomics.

[22]  T. Habuchi,et al.  Influence of CYP3A5 and MDR1 (ABCB1) Polymorphisms on the Pharmacokinetics of Tacrolimus in Renal Transplant Recipients , 2004, Transplantation.

[23]  C. Haisch,et al.  HLA matching and the united network for organ sharing allocation system: impact of HLA matching on african-american recipients of cadaveric kidney transplants , 2002, Transplantation.

[24]  M. Haberl,et al.  The genetic determinants of the CYP3A5 polymorphism. , 2001, Pharmacogenetics.

[25]  C. Young,et al.  Renal transplantation in black Americans. , 2000, The New England journal of medicine.

[26]  J. Neylan.  Effect of race and immunosuppression in renal transplantation: three-year survival results from a US multicenter, randomized trial. FK506 Kidney Transplant Study Group. , 1998, Transplantation proceedings.

[27]  J. Neylan.  Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group. , 1998, Transplantation.

[28]  C. Staatz,et al.  Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part I , 2010, Clinical pharmacokinetics.

[29]  C. Staatz,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation , 2004, Clinical pharmacokinetics.

[30]  P. Kimball,et al.  Influence of race on crossmatch outcome and recipient eligibility for transplantation. , 1992, Transplantation.