Optimizing tacrolimus dosage in post-renal transplantation using DoseOptimal framework: profiling CYP3A5 genetic variants for interpretability

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Abstract
Background Achieving optimal tacrolimus dosing is vital for effectively balancing therapeutic efficacy and safety, as CYP3A5 genetic variants and inter-patient variability emphasize the need for precision strategies. Aim This study aimed to optimize tacrolimus dosage prediction for renal transplant recipients by incorporating genetic polymorphisms, specifically profiling CYP3A5 genetic variants, within the DoseOptimal framework to enhance interpretability and accuracy of dosing decisions. Method The dataset comprised clinical, demographic, and CYP3A5 genetic variants information from 1045 stable tacrolimus-treated patients. The DoseOptimal framework was developed by integrating the strengths of the most effective algorithms from fifteen machine learning models. SHapley Additive exPlanations (SHAP) and decision tree insights were incorporated to enhance the framework’s interpretability. The framework’s performance was assessed using mean absolute error (MAE) and the coefficient of determination (R2 score). The F-statistic and p value were calculated to validate the framework’s statistical significance. Results The DoseOptimal framework demonstrated robust performance with an R2 score of 0.884 in the training set and 0.830 in the testing set. The MAE was 0.40 mg/day (95% CI 0.38–0.43) in the training set and 0.41 mg/day (95% CI 0.38–0.45) in the testing set. The framework predicted the ideal tacrolimus dosage in 87.6% (n = 275) of the test cohort, with 3.2% (n = 10) underestimation and 9.2% (n = 29) overestimation. The framework’s statistical significance was confirmed with an F-statistic of 266.095 and a p value < 0.001. Conclusion The framework provides precision medicine-based dosing solutions tailored to individual genetic profiles, minimizing dosing errors and enhancing patient outcomes.

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