Development of a clinically implementable population pharmacokinetic– pharmacodynamic model and interactive application for therapeutic drug monitoring of amrubicin

Background Amrubicin is an important chemotherapeutic agent for small cell lung cancer; however, severe neutropenia is a major dose-limiting toxicity. Exposure to its active metabolite, amrubicinol, correlates with neutropenia severity, suggesting its potential role in therapeutic drug monitoring (TDM). This study aimed to develop a clinically implementable pharmacokinetics (PK)–pharmacodynamics (PD) framework and an interactive web-based application to support amrubicin TDM using routinely available clinical data. Methods A previously published population PK–PD model of amrubicin was simplified to enhance its clinical applicability by removing the enterohepatic circulation component of amrubicinol metabolism and the associated genetic covariate. Model performance was evaluated using prediction-corrected visual predictive checks and nonparametric bootstrapping. An interactive web application was developed using R Shiny and RsNLME to simulate individual PK and neutrophil dynamics using empirical Bayes estimates derived from observed data. Results The updated model adequately described the plasma concentration-time profiles of amrubicin and amrubicinol as well as neutrophil dynamics. The prediction-corrected visual predictive checks demonstrated good agreement between the observed and simulated data. The robustness of the parameter estimates was confirmed using nonparametric bootstrapping. The finalized model was integrated into an interactive web application that supports individualized simulations of PK and neutrophil profiles using data observed during the first treatment cycle. Conclusion We developed a simplified and clinically applicable population PK–PD model and integrated it into an interactive web application for amrubicin TDM. This framework provides a practical foundation for prospective studies to evaluate model-informed strategies to mitigate severe neutropenia.