Applying machine learning to the pharmacokinetic modeling of cyclosporine in adult renal transplant recipients: a multi-method comparison

Abstract

Objective: The aim of this study was to identify the important factors affecting cyclosporine (CsA) blood concentration and estimate CsA concentration using seven different machine learning (ML) algorithms. We also assessed the predictability of established ML models and previously built population pharmacokinetic (popPK) model. Finally, the most suitable ML model and popPK model to guide precision dosing were determined. Methods: In total, 3,407 whole-blood trough and peak concentrations of CsA were obtained from 183 patients who underwent initial renal transplantation. These samples were divided into model-building and evaluation sets. The model-building set was analyzed using seven different ML algorithms. The effects of potential covariates were evaluated using the least absolute shrinkage and selection operator algorithms. A separate evaluation set was used to assess the ability of all models to predict CsA blood concentration. R squared (R ²) scores, median prediction error (MDPE), median absolute prediction error (MAPE), and the percentages of PE within 20% (F₂₀) and 30% (F₃₀) were calculated to assess the predictive performance of these models. In addition, previously built popPK model was included for comparison. Results: Sixteen variables were selected as important covariates. Among ML models, the predictive performance of nonlinear-based ML models was superior to that of linear regression (MDPE: 3.27%, MAPE: 34.21%, F₂₀: 30.63%, F₃₀: 45.03%, R ² score: 0.68). The ML model built with the artificial neural network algorithm was considered the most suitable (MDPE: -0.039%, MAPE: 25.60%, F₂₀: 39.35%, F₃₀: 56.46%, R ² score: 0.75). Its performance was superior to that of the previously built popPK model (MDPE: 5.26%, MAPE: 29.22%, F₂₀: 33.94%, F₃₀: 51.22%, R ² score: 0.68). Furthermore, the application of the most suitable model and the popPK model in clinic showed that most dose regimen recommendations were reasonable. Conclusion: The performance of these ML models indicate that a nonlinear relationship for covariates may help to improve model predictability. These results might facilitate the application of ML models in clinic, especially for patients with unstable status or during initial dose optimization.

Keywords: artificial neural network; cyclosporine; machine learning; population pharmacokinetic model; predictive performance; renal transplantation.