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

Background/Objectives: 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 develop a model-informed framework for assessing neutrophil dynamics using routinely available clinical data and pemetrexed exposure. Methods: This real-world investigation included 86 patients with NSCLC who received pemetrexed-platinum chemotherapy for model development, and 83 patients who received the same chemotherapy plus pembrolizumab or bevacizumab for validation. We developed a nonlinear mixed-effects 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 >175 μg·h/mL for pemetrexed, blood urea nitrogen, and concomitant use of renin-angiotensin system inhibitors influenced neutrophil suppression and delayed recovery. The receiver operating characteristic curve (AUROC) for identifying patients with a neutrophil count <1500/μL immediately before the anticipated next treatment cycle was 0.768 (95% CI: 0.639-0.898) in the development cohort, and 0.718 (95% CI: 0.545-0.891) in the validation cohort. Conclusions: This model-informed framework, based on PBPK-derived pemetrexed exposure and routinely available clinical factors, may help identify patients at risk of clinically relevant neutropenia that could delay the initiation of the next treatment cycle.