Target Tacrolimus Troughs and CYP3A5 Polymorphisms Do Not Predict Therapeutic Drug Exposure in African American and Caucasian Renal Transplant Recipients
1Pharmacy, School of Pharmacy, University at Buffalo(UB), Buffalo
2Biostatistics, RPCI, Buffalo
3Pharmaceutical Sciences, University of New England, Portland
4Nephrology, UB School of Medicine, Buffalo.
Meeting: 2018 American Transplant Congress
Abstract number: C105
Keywords: African-American, FK506, Immunosuppression, Kidney transplantation
Session Information
Date: Monday, June 4, 2018
Session Name: Poster Session C: Kidney Immunosuppression: Novel Regimens and Drug Minimization
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall 4EF
Background: African American(AA) renal transplant recipients(RTR) require larger tacrolimus(TAC) doses to achieve similar troughs to Caucasians which may be due to CYP3A5 polymorphisms. TAC pharmacokinetics exhibits interpatient variability requiring trough monitoring and racial investigation of corresponding area under concentration-time curves(AUC0-12hr) is limited. The relationship between TAC trough(target:4-9ng/ml),AUC0-12hr and CYP3A5 variants was investigated in 65 stable AA and Caucasian RTR >6 months post-transplant treated with TAC and mycophenolic acid.
Methods: 12-hour serial samples determined steady-state TAC AUC0-12 and 12hr troughs(C-12hr). The CYP3A5 polymorphisms: *3[rs776746],*6[10264272],*7[41303343], associated with loss of protein function, were characterized. RTR 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. Although 98.5% RTR achieved therapeutic troughs of 4-12ng/ml, 30 of 65(46.2%) patients had AUC0-12 < target 120-200 mg▪h/ml. More AA were in the desired AUC0-12 range than Caucasians. No association of CYP3A5 variants with RTR in or below AUC0-12 range was found.
| [dagger]=Mean±SD | AA [N=33] | C [N=32] | P-Value |
| TAC Dose(mg)[dagger] | 4.2±1.8 | 2.4±1.1 | <0.001 |
| TAC C-12hr(ng/ml)[dagger] | 7.8±1.8 | 6.7±1.8 | 0.010 |
| C-12hr at target:4-12 ng/ml | 33(100%) | 31(96%) | 0.49 |
| C-12hr below target | 1(3.1%) | ||
| TAC AUC0-12hr [dagger] | 137.0±78.9 | 114.6±28.0 | 0.005 |
| AUC0-12hr at target:120-200 mg▪hr/ml | 23(69.7%) | 12(37.5%) | 0.013 |
| AUC0-12hr below target | 10(30.3%) | 20(62.5%) | |
| Poor CYP3A5 | 6(18.2%) | 29(90.6%) | <0.001 |
| Intermediate CYP3A5 | 20(60.6%) | 3(9.4%) | |
| Extensive CYP3A5 | 7(21.1%) |
Conclusion: Most RTR attained therapeutic troughs but did not consistently achieve target tacrolimus AUC0-12hr with no association to CYP3A5 variants noted. Additional pharmacokinetic factors must be investigated.
CITATION INFORMATION: Tornatore K., Attwood K., Brazeau D., Chang S., Venuto R. Target Tacrolimus Troughs and CYP3A5 Polymorphisms Do Not Predict Therapeutic Drug Exposure in African American and Caucasian Renal Transplant Recipients Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Tornatore K, Attwood K, Brazeau D, Chang S, Venuto R. Target Tacrolimus Troughs and CYP3A5 Polymorphisms Do Not Predict Therapeutic Drug Exposure in African American and Caucasian Renal Transplant Recipients [abstract]. https://atcmeetingabstracts.com/abstract/target-tacrolimus-troughs-and-cyp3a5-polymorphisms-do-not-predict-therapeutic-drug-exposure-in-african-american-and-caucasian-renal-transplant-recipients/. Accessed March 8, 2021.« Back to 2018 American Transplant Congress