#1475 A Pharmacogenetic and body weight-informed predictive model for tacrolimus dosing in Taiwanese kidney transplant recipients

Abstract Background and Aims Tacrolimus is a key immunosuppressant in kidney transplantation, with a recommended starting dose of 0.1–0.15 mg/kg. Maintaining optimal tacrolimus levels is crucial, as excessive levels increase the risk of nephrotoxicity and infection, while insufficient levels heighten rejection risk. Dose variability is influenced by multiple factors, underscoring the need for personalized precision medicine. In clinical practice, adherence to Western dosing guidelines has led to a high incidence of tacrolimus levels exceeding 10 ng/mL during hospitalization post-transplant. Given ethnic differences in drug metabolism, particularly CYP3A5 polymorphisms, this study aims to establish an appropriate tacrolimus starting dose for Taiwanese kidney transplant recipients. Method From August 2018 to December 2023, all kidney transplant recipients at our hospital were included, excluding cases of thrombotic microangiopathy, ABO-incompatible transplants, donation after circulatory death, donor-specific antibody positivity, or Everolimus use within one year. All patients received an initial tacrolimus dose of 0.1–0.15 mg/kg with antithymocyte globulin induction therapy, along with corticosteroids and mycophenolate mofetil as standard immunosuppressive agents. Tacrolimus trough levels were monitored during hospitalization, documenting cases where levels exceeded 10 ng/mL and required dose reduction. The target trough level (6–10 ng/mL) was maintained throughout the first postoperative year, with the annual tacrolimus dose normalized to body weight (mg/kg). Patients were categorized based on CYP3A5 pharmacogenetic polymorphisms into normal, intermediate, and poor metabolizers. The one-year average tacrolimus dose (mg/kg) among pharmacogenetic groups was compared using the Kruskal-Wallis test, with results reported as median [25th, 75th percentiles]. A series of univariate linear regression analyses firstly screened the potential association of patient characteristics, including continuous variables (age, body weight, BMI, dialysis duration) and categorical variables (weight status and pharmacogenetic classification). Since body weight and pharmacogenetic classification were significantly associated with tacrolimus dosing, a multivariable linear regression model was developed to predict the required tacrolimus dose. Results A total of 56 kidney transplant recipients were included in the study, among whom 36 patients (64.2%) required tacrolimus dose reduction during hospitalization due to supratherapeutic levels. Pharmacogenetic testing revealed that 7 patients were CYP3A5 normal metabolizers, 20 were intermediate metabolizers, and 29 were poor metabolizers. The one-year average tacrolimus dose (mg/kg) was significantly lower in the poor metabolizers (0.04 [0.03, 0.06] mg/kg) than that in the normal (0.10 [0.09, 0.13] mg/kg) and intermediate metabolizers (0.10 [0.08, 0.11] mg/kg). The multivariable analysis showed that body weight (regression coefficient [B] = −0.0012, 95% CI: −0.0017 to −0.0007) and dichotomous pharmacogenetic classification (B = −0.0444, 95% CI: −0.0603 to −0.0285), with a variance explained by 50.3%. The derived predicted tacrolimus dose (mg/kg) = 0.181–0.0012 × body weight –0.0444 × gene status; where gene status: 1 = poor metabolizer, 0 = normal/intermediate metabolizer. Conclusion This study presents the first predictive model for tacrolimus starting dose in Taiwanese kidney transplant recipients, demonstrating that CYP3A5 polymorphisms significantly impact dose requirements, with poor metabolizers requiring lower doses. The proposed dosing formula enables personalized tacrolimus initiation, optimizing immunosuppressive therapy while minimizing toxicity and rejection risks. Despite the limitation of a small sample size, this preliminary study underscores the need for larger-scale validation and serves as a valuable reference for individualized tacrolimus dosing, advancing precision medicine in transplantation.