Date: Sunday, June 6, 2021
Session Time: 7:30pm-8:30pm
Presentation Time: 7:30pm-7:40pm
*Purpose: Tacrolimus (TAC) metabolism is dependent on the functional status of the cytochrome P450 family enzyme CYP3A5 which has three common loss of function (LoF) genetic alleles *3, *6, and *7. Presence of the functional CYP3A5*1 allele has been linked to increased tacrolimus dose, risk of rejection and graft loss. We hypothesized that patients with one or two CYP3A5*1 alleles would require a greater number of TAC dose adjustments and troughs measured relative to patients without a *1 allele.
*Methods: This was a retrospective review of kidney transplant recipients from a single center participating in the GEN03 study with available genotype data for CYP3A5 *1 *3, *6, and *7 and at least 6 months of TAC information. The primary endpoints were number of TAC dosage adjustments and trough levels measured in the first six months, and data were analyzed using quasi-likelihood based Poisson regression. Secondary endpoints included incidence of biopsy proven acute rejection (BPAR) and estimated glomerular filtration rate (eGFR) at 1, 3, and 6 months post-transplant.
*Results: 78 patients had available CYP3A5 genotype data and were included. Fifty-five patients were CYP3A5 poor metabolizers (PM, carriers of two LoF alleles), 17 were intermediate metabolizers (IM, carriers of one LoF allele), and 6 were extensive metabolizers (EM, no LoF alleles). Compared to PMs, EMs were more likely to require more trough measurements and dosage adjustments, RR 1.2 [95% CI 1.00-1.44] and RR 1.53 [95% CI 1.11-2.11] respectively. No differences in number of troughs or dosage adjustments were observed between PMs and IMs. Incidence of BPAR was low with 1 PM and 1 EM experiencing rejection. At 6 months, mean (SD) eGFR in mL/min/1.73m2 was 60.5 (20.3) for PMs, 64.1 (16.7) for IMs, and 43.8 (13.5) for EMs. PMs had significantly higher eGFR than EMs (p = 0.047).
*Conclusions: CYP3A5 EMs required more dose adjustments and additional trough measurements relative to PMs. Although changes in graft outcomes were not different among the metabolizer groups, the frequency of the events was low. Further research is warranted to investigate whether initial TAC dosing optimized based on CYP3A5 genotypes would reduce cost of care, result in better goal attainment, and improve time to the therapeutic range.
To cite this abstract in AMA style:Reininger K, Onyeaghala G, Anderson-Haag T, Wu B, Guan W, Dorr CR, Remmel R, Mannon R, Matas A, Oetting W, Israni A, Stahler P, Jacobson P. Higher Number of Tacrolimus Dose Adjustments and Trough Level Measurements in Kidney Transplant Recipients with CYP3A5*1 Alleles [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/higher-number-of-tacrolimus-dose-adjustments-and-trough-level-measurements-in-kidney-transplant-recipients-with-cyp3a51-alleles/. Accessed September 23, 2021.
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