P3A.07: Impact of Donor and Recipient CYP3A5 and ABCB1 Genotype on Tacrolimus Trough/Dose Ratios Following Intestinal Transplant

Abstract

Introduction: Tacrolimus (TAC) is a mainstay of immunosuppression after intestinal transplantation (ITX), but dosing is complicated by a narrow therapeutic index and broad variability. Studies in kidney and liver transplantation have identified the influence of CYP3A5 and ABCB1 genetic variants, both of which are expressed in the intestinal epithelium, on TAC pharmacokinetics; however, no studies have examined the influence of pharmacogenetic (PGX) variation on TAC exposure in ITX. Methods: This was a single-center, retrospective analysis of adult ITX recipients from 2011–2018. Patients were included if they received a non-liver containing ITX, maintained graft function for 3 months, and had donor and recipient tissue samples stored. DNA was isolated from sample tissue and multiplexed genotyping of CYP3A5*2,*3,*7 and ABCB1c.3435C>T was performed. Donors or recipients with a *1 allele were CYP3A5 expressers, while patients with a CC genotype were ABCB1 expressers. A combined analysis was also performed that grouped patients by total donor and recipient CYP3A5 and ABCB1 allele score. Weight-normalized TAC trough:dose (T/D) ratios were assessed for each patient during month 1 and at 4, 12, and 52 weeks post-ITX. The primary outcome was difference in mean T/D ratios between the genotypes across time points. Results: A total of 31 patients were included in the analysis (Table 1). After genotyping, 22.6% of recipients and 32.3% of donors were CYP3A5 expressers; and 35.5% of recipients and 25.8% of donors were ABCB1 expressers. Donor or recipient expressers of CYP3A5 or ABCB1 had lower T/D ratios at 4, 12, and 52 weeks relative to non-expressers (Figure 1). When both donor and recipient genotype were considered for CYP3A5 and ABCB1, combined non-expressers had the highest T/D ratios, indicating lower dosing requirements. Based on allele score, 5 patients were classified as low score (≤1 active allele), 14 patients were moderate score (2–3 active alleles), and 12 patients were high score (≥4 active alleles). Patients with low allele scores had the highest T/D ratios as well as the highest percentage of therapeutic TAC levels within 1 month of ITX (53.2%vs34.4%vs38.9%;p=0.04). Conclusion: In the first study evaluating PGX in ITX, our results suggest that both donor and recipient CYP3A5 and ABCB1 expression impact TAC dosing. When both genotypes are combined it may be possible to predict patients at high risk for subtherapeutic TAC dosing.