Tacrolimus Therapeutic Exposure is Not Consistently Predicted by Target Troughs or CYP3A5 Variants in Stable Renal Transplant Recipients
1Pharmacy Practice, School of Pharmacy
University at Buffalo, Buffalo, NY, 2Biostatistics, School of Public Health
University at Buffalo, Buffalo, NY, 3Pharmacy Practice, School of Pharmacy
Marshall University, Huntington, WV, 4Medicine, Erie County Medical Center Corp., Buffalo, NY
Meeting: 2021 American Transplant Congress
Abstract number: 421
Keywords: Area-under-curve (AUC), Kidney transplantation, Monitoring, Pharmacokinetics
Topic: Clinical Science » Pharmacy » Non-Organ Specific: Pharmacogenomics / Pharmacokinetics
Session Information
Session Name: Pharmacokinetics, Pharmacogenetics, and Drug Interactions, Oh My!
Session Type: Poster Video Chat
Date: Sunday, June 6, 2021
Session Time: 7:30pm-8:30pm
Presentation Time: 8:00pm-8:10pm
Location: Virtual
*Purpose: Tacrolimus (TAC) immunosuppression requires therapeutic trough monitoring post-transplant due to notable interpatient pharmacokinetic(PK) variability which may be attributed to CYP3A5 polymorphisms. We investigated the relationship of therapeutic tacrolimus troughs to the corresponding drug exposure with CYP3A5 variants in stable renal transplant recipients(RTR) on long-term immunosuppression.
*Methods: The relationship between tacrolimus troughs(target: 4-12ng/ml) and Area Under the Concentration Time Curve 0-12 hours (AUC 0-12hr) with target exposure of 120 to 200 ng▪hr/ml, and CYP3A5 variants was investigated in 65 stable RTR treated with maintenance immunosuppression of immediate release tacrolimus and mycophenolic acid. A prospective study collected 12-hour serial samples for determination of steady-state tacrolimus PK including: AUC 0-12hr, 12hr troughs(C-12hr) and clearance(CL). The C-12hr were achieved using therapeutic drug monitoring. 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 CYP3A5*3*6*7 metabolic composites based on functional genotypes and analyzed with tacrolimus PK using SAS V 9.4.
*Results: The table below summarizes the RTR according to AUC 0-12hr greater than 120 ng▪hr/ml and less than 120 ng▪hr/ml. The combined groups had mean eGFR: 55.8 (15.5) ml/min/1.73m2 and time post-transplant: 3.0(2.6) years. Therapeutic troughs of 4-12ng/ml were achieved in 98.5% of RTR with 53.9% of recipients within the therapeutic AUC 0-12hr and 44.6% below the therapeutic exposure (P < <0.001). No difference in CL between groups was noted. No association of CYP3A5*3*6*7 composite was found within or below AUC 0-12 range.
*Conclusions: Although stable RTR achieved the trough targets using therapeutic drug monitoring, approximately 45% of these recipients were below the recommended tacrolimus AUC 0-12hr. The composite CYP3A5*3*6*7 variants demonstrated no predictive associations toward achieving the therapeutic target exposure.
| +=Mean(SD); #: N(%Freq) | Less than 120 AUC 0-12hr [N=30] | Greater or equal to 120 AUC 0-12hr [N=35] | P Value |
| Race W: White; B:Black | B: 10(33.3%); W: 20(60%) | B:23(65.7%);W:12(34.3%) | 0.013 |
| TAC Dose(mg)+ | 3.0(1.8) | 3.7 (1.6) | 0.02 |
| TAC C-12hr(ng/ml)+ | 6.0 (1.3) | 8.3 (1.5) | < <0.001 |
| TAC AUC 0-12hr (ng▪hr/ml)+ | 99.5 (16.6) | 148.7 (22.8) | < <0.001 |
| Poor CYP3A5 Com # | 17(56.7%) | 18(51.4%) | 0.94 |
| Intermediate CYP3A5 Com # | 10(33.3%) | 13(37.1%) | – |
| Extensive CYP3A5 Com # | 3(10%) | 4(11.4%) | – |
To cite this abstract in AMA style:
Tornatore K, Attwood K, Brazeau D, Murray B. Tacrolimus Therapeutic Exposure is Not Consistently Predicted by Target Troughs or CYP3A5 Variants in Stable Renal Transplant Recipients [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/tacrolimus-therapeutic-exposure-is-not-consistently-predicted-by-target-troughs-or-cyp3a5-variants-in-stable-renal-transplant-recipients/. Accessed November 21, 2024.« Back to 2021 American Transplant Congress