Induction of Tacrolimus Clearance by Steroids Varies by Cyp3a5 Genotype in Kidney Transplant Recipients: A Drug-Drug-Gene Interaction
1Univ of MN, College of Pharmacy, Minneapolis, MN, 2Hennepin Health Research Institute, Minneapolis, MN, 3Univ of MN, Biostatistics, Minneapolis, MN, 4Univ of Nebraska, Dept of Medicine, Omaha, NE, 5Hennepin Health Research Institute and Dept of Medicine, Minneapolis, MN, 6Hennepin Healthcare Research Institute, Minneapolis, MN, 7Hennepin Health Dept of Medicine and Univ of MN, Minneapolis, MN, 8University of MN, Dept of Surgery, Minneapolis, MN
Meeting: 2022 American Transplant Congress
Abstract number: 503
Keywords: Drug interaction, Genomic markers, Immunosuppression, Pharmacokinetics
Topic: Clinical Science » Kidney » 49 - Recurrent Kidney Disease & Genetics
Session Information
Session Name: Recurrent Kidney Disease & Genetics
Session Type: Rapid Fire Oral Abstract
Date: Tuesday, June 7, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 6:10pm-6:20pm
Location: Hynes Room 310
*Purpose: Tacrolimus (TAC) is the primary immunosuppressant used in organ transplantation. TAC is a substrate for CYP3A4/5. These enzymes are inhibited or induced by multiple concomitantly administered drugs leading to high variability in blood concentrations and need for therapeutic drug monitoring. It is well-known that concomitant steroid use induces tacrolimus clearance (CL); however the extent of the induction varies among individuals. We hypothesized that induction of CYP enzymes by steroids and a resulting increase in TAC CL was greater in individuals carrying functional CYP3A5 alleles than those with nonfunctional alleles.
*Methods: We evaluated 28994 TAC troughs and doses (18424 with steroids and 10547 without steroids) from 1620 kidney transplant recipients (52 Asians, 267 African Americans, 34 Native Hispanic, 1267 Caucasians) with CYP3A genotype data (CYP3A5 loss of function alleles [LOF] *3, *6, *7) available from a GWAS chip. Presence or absence of a concomitant steroid was obtained for each trough. Nonlinear mixed effect modeling (NONMEM) was used to evaluate the effect of steroids as a time-varying covariate on TAC clearance (CL) across CYP3A5 genotypes while accounting for other important clinical factors.
*Results: Zero, one and two LOF alleles were present in 70, 331 and 1219 recipients, respectively. No recipient carried CYP3A5*7/*7. In the absence of steroids, CYP3A5*1/*1 followed by CYP3A5*1/*6 showed the highest TAC CL. Steroids induced TAC CL but varied by CYP3A5 genotype. CYP3A5*1/*1 carriers had a 39% higher TAC CL while receiving steroids vs when not receiving a steroid. Individuals with CYP3A5*1/*3 and *1/*6 had a 25% and 34%, respectively, increase in TAC CL during steroid treatment. Whereas individuals with CYP3A5*3/*3 had only an 11% increase in TAC CL when receiving a steroid compared to no steroid.
*Conclusions: TAC CL in individuals with CYP3A5 *1 and *6 alleles are more profoundly affected by steroid induction of CYP3A enzymes than carriers of the *3 allele. Individuals of African ancestry may be more likely to be affected by this drug-drug-gene interaction since they have a higher frequency of these alleles. Steroid dose should be evaluated for its effect on this interaction.
To cite this abstract in AMA style:
Jacobson PA, Saqr A, Al-Kofahi M, Schladt DP, Guan W, Oetting WS, Mannon R, Dorr CR, Remmel RP, Onyeaghala GC, Wu B, Israni AK, Matas A. Induction of Tacrolimus Clearance by Steroids Varies by Cyp3a5 Genotype in Kidney Transplant Recipients: A Drug-Drug-Gene Interaction [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/induction-of-tacrolimus-clearance-by-steroids-varies-by-cyp3a5-genotype-in-kidney-transplant-recipients-a-drug-drug-gene-interaction/. Accessed May 18, 2025.« Back to 2022 American Transplant Congress