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Serplulimab is a fully humanized anti–PD‐1 monoclonal antibody approved for small‐cell lung cancer and other malignancies. The initial dosing strategy was based on body weight (WT‐based); however, flat‐dosing offers greater convenience and reduced variability. This study characterized the population pharmacokinetics (PopPK) of serplulimab using data from 11 clinical trials and quantitatively evaluated the appropriateness of transitioning from WT‐based to flat‐dose regimens. Serplulimab concentration–time data from 2110 patients were analyzed using nonlinear mixed‐effects modeling. A previously developed two‐compartment model with time‐varying clearance best described the pharmacokinetic (PK) profile. A stepwise forward‐addition and backward‐elimination procedure was used to evaluate covariate effects on PK parameters. Model adequacy was confirmed by diagnostic plots, prediction‐corrected visual predictive checks (pcVPCs), and bootstrap analysis. Simulations compared exposures between 3 mg/kg every 2 weeks (Q2W), 4.5 mg/kg every 3 weeks (Q3W), 200 mg Q2W, and 300 mg Q3W regimens. Body weight and albumin were the main predictors of exposure. Although statistically significant, covariate effects were modest (≤ 20%) and not clinically meaningful, supporting a unified dosing strategy. Simulations showed that flat‐dose regimens achieved exposure comparable to WT‐based dosing, with < 25% differences in median Cavg and Cmax across body‐weight ranges. Exposure–response (E–R) analyses revealed no meaningful association between exposure and outcomes. The PopPK model adequately described serplulimab PK and supports transitioning from WT‐based to flat‐dosing, demonstrating comparable exposure, efficacy, and safety across regimens. Study Highlights What is the current knowledge on the topic? ○Flat‐dosing of monoclonal antibodies can provide comparable exposure as WT‐based dosing while simplifying their clinical use, but quantitative justification is needed for each specific agent. What question did this study address? ○Can flat‐dose regimens of serplulimab achieve similar PK exposure, efficacy, and safety as WT‐based dosing across broad patient populations? What does this study add to our knowledge? ○PopPK and E‐R analyses showed comparable exposure and clinical outcomes between flat and WT‐based dosing, with covariate effects ≤ 20% and not clinically meaningful. How might this change clinical pharmacology or translational science? ○The findings quantitatively support flat‐dosing of serplulimab, reinforcing the shift toward simplified, standardized dosing strategies for monoclonal antibodies in oncology.

While PD‐L1 antibodies have demonstrated efficacy in small cell lung cancer, the therapeutic benefits remain limited. To address this unmet medical need, serplulimab was developed as an innovative monoclonal antibody targeting PD‐1. This study evaluated the pharmacokinetic (PK) properties of serplulimab and their relationship with efficacy and safety in patients with extensive‐stage small cell lung cancer (ES‐SCLC), using population pharmacokinetics (PopPK) and exposure–response (E–R) analysis to inform dose selection. Data from 1144 patients across eight Phase I–III clinical trials supported a two‐compartment PopPK model with time‐dependent clearance. Cox proportional hazards models were employed to analyze the correlation between exposure (Cavg1 and Cmin1) and overall survival (OS)/progression‐free survival (PFS), and adverse events (AEs) with exposure (Cavg1 and Cmax1). Body weight, albumin (ALB), and gender significantly influenced the clearance and volume distribution of serplulimab; however, the observed differences in exposure ratio did not reach clinically relevant thresholds (0.8–1.25), thereby obviating the need for dose adjustments. Safety analysis revealed no monotonic increase in AE probability with increasing exposure (p > 0.05). Efficacy analysis indicated no significant correlation between exposure and OS (p > 0.05), whereas lactate dehydrogenase (LDH) and tumor burden emerged as significant predictors of OS (p < 0.05). Results confirm favorable PK and safety of serplulimab at the recommended dose, requiring no adjustment for above covariates. These findings suggest that the current dose is on the plateau of the E–R curve, and dose escalation is unlikely to improve clinical outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT03952403, NCT04818359, NCT05246164, NCT04747236, NCT03973112, NCT04297995, NCT04778904, NCT04063163