Integrating pharmacogenetic and clinical factors to predict the C0/D/W-based tacrolimus phenotype in kidney transplantation.

Background: Tacrolimus shows substantial interindividual pharmacokinetic variability, complicating dose individualization in renal transplantation. The tacrolimus trough concentration-to-dose-to-weight ratio (C0/D/W) has been proposed as a simple surrogate of tacrolimus bioavailability, yet the extent to which pharmacogenetic and clinical factors explain this phenotype in stable adult kidney transplant recipients remains unclear. Methods: We conducted a single-centre retrospective study including 77 adult renal transplant recipients treated with prolonged-release tacrolimus formulations (Advagraf® or Envarsus®) and clinically stable. Tacrolimus exposure phenotype was defined using C0/D/W tertiles: the lowest tertile was classified as the high-metabolism phenotype and the highest tertile as the low-metabolism phenotype. Genotyping was performed using a customized OpenArray panel. The predictive performance of CYP3A5 rs776746 alone was assessed using diagnostic accuracy metrics. Multivariable logistic regression models integrating clinical covariates and genotype-based exposure scores were developed. Model performance was evaluated using McFadden's pseudo-R Results: The high- and low-metabolism groups comprised 39 and 38 patients, respectively. CYP3A5 expresser genotypes (*1 carriers) identified high-metabolism phenotype with a sensitivity of 48.7% and a specificity of 89.5%, yielding an overall accuracy of 68.8%. In multivariable analysis, CYP3A5 rs776746 score, age, and post-transplant period were associated with metabolism phenotype. The primary parsimonious model demonstrated good discrimination (apparent AUC 0.83; 95% CI 0.73-0.92), with an optimism-corrected AUC of 0.80 and a McFadden pseudo-R Conclusion: CYP3A5 genotype alone provides high specificity but limited sensitivity for predicting tacrolimus C0/D/W-based metabolism phenotype. Incorporation of key clinical variables, including age and time since transplantation, improves phenotype discrimination and provides a more comprehensive characterization of tacrolimus exposure variability. Additional pharmacogenetic markers showed limited incremental value. These findings support a combined genetic-clinical approach for tacrolimus dose individualization, although external validation in larger cohorts is warranted.