Kidney Week

Abstract: SA-PO633

Tacrolimus Troughs and Doses in African American, Asian, Caucasian, and Hispanic/Native American Kidney Transplant (tx) Recipients

Session Information

• Pharmacology
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Jacobson, Pamala A., University of Minnesota, Minneapolis, Minnesota, United States

Pamala A. Jacobson,

• Schladt, David P., Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States

David P. Schladt,

• Oetting, William S., University of Minnesota, Minneapolis, Minnesota, United States

William S. Oetting,

• Wu, Baolin, University of Minnesota, Minneapolis, Minnesota, United States

Baolin Wu,

• Guan, Weihua, University of Minnesota, Minneapolis, Minnesota, United States

Weihua Guan,

• Dorr, Casey R., Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States

Casey R. Dorr,

• Remmel, Rory P., University of Minnesota, Minneapolis, Minnesota, United States

Rory P. Remmel,

• Mannon, Roslyn B., University of Alabama at Birmingham, Birmingham, Alabama, United States

Roslyn B. Mannon,

• Ikle, David N., Rho Federal Systems Division, Chapel Hill, North Carolina, United States

David N. Ikle,

• Matas, Arthur J., University of Minnesota, Minneapolis, Minnesota, United States

Arthur J. Matas,

• Israni, Ajay K., Hennepin County Medical Center, Minneapolis, Minnesota, United States

Ajay K. Israni,

Group or Team Name

• DeKAF Genomics

Background

TAC is an immune suppressant with a narrow therapeutic index and high inter-individual pharmacokinetic (PK) variability. African Americans (AA) have lower troughs and higher dose requirements primarily due to the CYP3A5*1 allele that results in CYP3A expression. Caucasians have higher troughs and lower dose requirements due to the loss of function variants CYP3A5*3 and CYP3A4*22. TAC trough and genotype relationships for Asian and Hispanic/Native Americans are not well described.

Methods

2739 adult kidney tx recipients enrolled in the multicenter DeKAF Genomics and the GEN03 genome wide association studies (GWAS) who received TAC maintenance and had TAC troughs available in the first 6 mo posttx were studied. Race was identified and confirmed through principal component analysis using the GWAS. We tested the association between genetic variants (CYP3A5*3, *6 and *7, CYP3A4*22) and dose-normalized TAC troughs in each population adjusting for center, age and gender

Results

The allele frequency of CYP3A5*3 differed between the groups; 0.30, 0.72, 0.92, 0.84 in AA, Asian, Caucasian and Hispanic/Native Americans, respectively. The median (IQR) TAC dose-normalized trough, dose and trough by population are in the table. CYP3A5*3 was highly significant in all groups (p = 3.3E-09 to 4.9E-127). CYP3A5*6 and *7 were associated with troughs in the AA group (p=2.0E-12 and 1.3E-24) and CYP3A4*22 in the Caucasian group (2.2xE-22).

Conclusion

The Hispanic/Native American group had the highest dose-normalized TAC trough and the AA the lowest. The most rapid TAC metabolism occurs in AA followed by Asians, Caucasians and Hispanic/Native Americans. Genetic variants that influence TAC metabolism are highly significant and vary by race. This data suggest that additional variants may be present in the Asian and Hispanic/Native American groups which impact CYP3A4 and 5 substrate metabolism.