Clinical significance and gene prediction of a novel classification system based on tacrolimus concentration-to-dose ratio in the early post-liver transplant period

Abstract

Background and aims: Classification system of tacrolimus elimination and its clinical significance has not been well described in liver transplantation. This study aimed to present a novel tacrolimus clearance clinical-FIS (Fast-Intermediate-Slow) classification and its gene prediction system.

Methods: Patients from 3 transplant centers were enrolled in this study. All recipients and their corresponding donor livers from center 1 were genotyped using an Affymetrix DMET Plus microarray, and association analysis was performed using trough blood concentration/weight-adjusted-dose ratios (CDR, (ng/mL)/(mg/kg)). The candidate-associated loci were then sequenced in center 2 and center 3 patients for verification.

Results: A clinical classification based on tacrolimus CDR can effectively divide liver transplantation patients into fast elimination (FE), intermediate elimination (IE), and slow elimination (SE) groups, which we called the clinical-FIS classification. Trough blood concentrations in the clinical-SE group during the early postoperative period were higher than those in the clinical-FE and clinical-IE groups, which could lead to delayed recovery of liver (P = 0.0373) and kidney function (P = 0.0135) and a higher infection rate (P = 0.0086). The prediction accuracy of the current CPIC (Clinical Pharmacogenetics Implementation Consortium)-EIP metabolizer classification based on recipient CYP3A5 rs776746 genotype for clinical-FIS classification was only 35.56%. A newly established genetic-EIP classification including major effect genetic factors (donor and recipient CYP3A5 rs776746) and minor effect genetic factors (recipient SULT1E1 rs3775770 and donor SLC7A8 rs7141505) showed 73.2% overall consistency with the former clinical FIS classification.

Conclusion: Our study presented a novel tacrolimus clearance classification, clinical-FIS, and then proposed a novel prospective genetic-EIP classification as a genotyping basis for precisely predicting the clinical-FIS.

Keywords: drug metabolism; gene polymorphism; liver transplantation; personalized medicine; tacrolimus.

FIGURE 1

Overall research framework. CPIC-EIP, paired-EIP, and genetic-EIP classification were established base on both genetic and clinical information successively and compared with clinical-FIS classification based only on clinical data. ① CPIC-EIP proposed by Clinical Pharmacogenetics Implementation Consortium includes donor or recipient CYP3A5 rs776746 loci only. ② paired-EIP were validated in our study includes both donor and recipient CYP3A5 rs776746 loci. ③ Genomics-EIP presented in this study includes other minor effect loci besides donor and recipient CYP3A5. ④ Clinical-FIS were firstly proposed in this study and only based on clinical CDR.

FIGURE 2

Clinical characteristics of patients in different groups under clinical-FIS classification. (A) The changing curves of dose-adjusted trough blood concentrations in FE, IE and SE group at 28 days postoperatively. (B) The weight-adjusted dose of each group based on this retrospective clinical-FIS classification can be effectively distinguished. The dose of tacrolimus was low at the outset and was generally increased 1 or 2 weeks after the operation, reaching a plateau. (C) The changing curves of concentrations in FE, IE and SE group at 28 days postoperatively. (D) The median of alanine aminotransferase in clinical-FE, clinical-IE and clinical-SE group patients in the first postoperative week was 121.7 U/L, 146.4 U/L and 191.1 U/L respectively, with significant differences (P = 0.0373) among the three groups. (E) The median of serum creatinine in clinical-FE, clinical-IE and clinical-SE group patients in the first postoperative week was 57.75 μmol/L, 58.5 μmol/L and 74.0 μmol/L respectively, also with significant differences (P = 0.0135) among the three groups. If you prefer, you can place both the actual figures and captions logically through the text near where they are cited rather than at the end of the file (but not both). (F) The percentage of recipients carrying higher leukocyte count in clinical-FE (6.52%, 3/46), clinical-IE (7.22%, 7/97) and clinical-SE (22.6%, 12/53) group patients in the first postoperative week than normal, with significant differences among the three groups (P = 0.0086). (G) The percentage of recipients with bacterial infection in clinical-FE (28.3%, 13/46), was obviously lower than that in clinical-IE (45.6%, 41/90) and clinical-SE (48.8%, 21/43) group respectively, and there were no significant differences among the three groups (P = 0.0881). (H) The percentage of recipients with rejection reaction in clinical-FE, clinical-IE and clinical-SE group patients in the follow-up period was 21.7% (10/46), 21.1% (19/90) and 11.6% (5/43) respectively, and there were no significant differences among the three groups (P = 0.3672).

FIGURE 3

Comparison of daily tacrolimus dose requirements (mg/day) at postoperative week 4 across different metabolic classification systems:Clinical FIS phenotyping (Slow/Intermediate/Fast), Donor CYP3A5 rs776746 genotype, Recipient CYP3A5 rs776746 genotype, Combined donor-recipient CYP3A5 rs776746, Novel EIP genotyping. Boxplots show median (central line), IQR (box), and range (whiskers). Kruskal–Wallis test with Dunn’s correction was used for group comparisons.