Association of CYP3A5*3*6*7 Metabolic Composites to Tacrolimus Pharmacokinetics in African American and Caucasian Renal Transplant Recipients
1Pharmacy, School of Pharmacy, University at Buffalo(UB), Buffalo
2Pharmaceutical Sciences, College of Pharmacy
University of New England, Portland
3Biostatistics, Roswell Park Cancer Institute, Buffalo
4Biostatistics, UB School of Public Health, Buffalo
5Nephrology, UB School of Medicine, Buffalo.
Meeting: 2018 American Transplant Congress
Abstract number: A54
Keywords: FK506, Genomic markers, Immunosuppression, Pharmacokinetics
Session Information
Session Name: Poster Session A: Biomarkers, Immune Monitoring and Outcomes
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background: Interpatient variability in tacrolimus pharmacokinetics(PK) is due primarily to metabolism by cytochrome P-450 3A5(CYP3A5) isoenzymes. African Americans(AA) require higher tacrolimus doses to achieve comparable troughs to Caucasians(C) which may be attributed to different CYP3A5 variants. The associations of CYP3A5*3*6*7 variants to tacrolimus PK were investigated in 65 stable AA and C receiving tacrolimus and mycophenolic acid >6 months post-renal transplant.
Methods: 12-hour serial samples determined steady-state tacrolimus PK including trough, oral clearance(CL), area under concentration-time curve(AUC0-12) and AUC0-12/Dose(AUC*). The CYP3A5 polymorphisms:*3[rs776746],*6[10264272],*7[41303343], associated with loss of protein function were characterized. Patients were classified as Extensive, Intermediate and Poor metabolizers using the novel CYP3A5*3*6*7 metabolic composites based on functional genes present and analyzed by SAS V 9.4.
Results: Table 1 summarizes the results. 88% of AA were classified as Extensive or Intermediate metabolizers requiring 1.6 to 2.2 fold higher tacrolimus doses to account for more rapid clearance. The remaining AA exhibited the loss of function variants which were associated with lower tacrolimus doses and slower clearance compared to Caucasians.
| Tacrolimus PK:Mean±SD | Poor [N=35:29C;6AA] | Intermediate [N=23:3C;20AA] | Extensive [N=7 AA] | P-Value |
| Dose(mg) | 2.46±1.1 | 4.07±1.57 | 5.64±1.60 | <0.001 |
| Trough(ng/ml) | 6.99±1.83 | 7.70±1.88 | 6.77±1.67 | 0.550 |
| AUC0-12(ng.hr/ml) | 119.7±28.7 | 135.8±35.1 | 125.7±31.3 | 0.261 |
| AUC0-12*(ng.hr/ml/mg) | 56.0±24.7 | 37.1±12.8 | 24.3±10.8 | <0.001 |
| Clearance(L/hr) | 21.1±8.02 | 30.8±12.2 | 47.4±17.3 | <0.001 |
Conclusions: This is the first report describing the CYP3A5*3*6*7 metabolic composite and provides insight into the overall contribution of these polymorphisms to variable tacrolimus PK in African American and Caucasian renal transplant recipients.
CITATION INFORMATION: Tornatore K., Brazeau D., Meaney C., Attwood K., Wilding G., Chang S., Venuto R. Association of CYP3A5*3*6*7 Metabolic Composites to Tacrolimus Pharmacokinetics in African American and Caucasian Renal Transplant Recipients Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Tornatore K, Brazeau D, Meaney C, Attwood K, Wilding G, Chang S, Venuto R. Association of CYP3A5*3*6*7 Metabolic Composites to Tacrolimus Pharmacokinetics in African American and Caucasian Renal Transplant Recipients [abstract]. https://atcmeetingabstracts.com/abstract/association-of-cyp3a5367-metabolic-composites-to-tacrolimus-pharmacokinetics-in-african-american-and-caucasian-renal-transplant-recipients/. Accessed November 21, 2024.« Back to 2018 American Transplant Congress