Prediction of Neutropenia Risk Based on Exposure Information Without Plasma Concentration Measurement in Pemetrexed‒Platinum‒Based Chemotherapy: A Modeling Approach Using Real-World Clinical Data

Purpose Pemetrexed‒platinum chemotherapy is a key treatment option for non-squamous non-small cell lung cancer (NSCLC); however, its use is often limited by hematologic toxicity, particularly neutropenia. We aimed to model neutrophil dynamics following pemetrexed‒platinum chemotherapy using clinical data routinely available for patients and pharmacokinetic parameters of pemetrexed. Methods This real-world investigation included 86 patients with NSCLC who received pemetrexed‒platinum chemotherapy for model development, and an additional 83 patients who received the same chemotherapy plus pembrolizumab or bevacizumab as a validation cohort. We developed a nonlinear mixed-effects (NLME) model to predict neutrophil dynamics during the first cycle following pemetrexed‒platinum chemotherapy, using patient-specific clinical data collected before chemotherapy initiation and pemetrexed pharmacokinetic parameters derived from physiologically based pharmacokinetic (PBPK) modeling. Results The final model suggested that the area under the curve (AUC) _0–24 of pemetrexed, blood urea nitrogen value, and concomitant use of renin‒angiotensin system inhibitors influenced neutrophil suppression and delayed recovery. The goodness-of-fit plots, visual predictive check, nonparametric bootstrap analysis, and receiver operating characteristic (ROC) curves demonstrated good fit and high performance, with an area under the ROC curve (AUROC) of 0.92 for predicting severe neutropenia. The model maintained good performance in the validation cohort receiving antibody-containing regimens (AUROC 0.85). Conclusion This study demonstrated the importance of considering exposure to pemetrexed for an early prediction of neutropenia following pemetrexed‒platinum chemotherapy. Our model supports proactive pemetrexed dose optimization to prevent severe neutropenia, minimize treatment delays or interruptions, and preserve overall treatment intensity in patients undergoing pemetrexed‒platinum chemotherapy.