Population Pharmacokinetic Analyses and Exposure–Efficacy Relationships of Venetoclax in Chinese Pediatric Patients with Hematological Malignancy in a Real‐World Setting

Background: Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, is used in pediatric hematologic malignancies. Research on individualized VEN therapy in Chinese pediatric patients remains limited. This study aimed to develop a population pharmacokinetic (PPK) model in Chinese pediatric patients, identify covariates influencing pharmacokinetics, support personalized dosing, and explore exposure-efficacy relationships in pediatric acute myeloid leukemia (AML). Methods: PPK modeling was based on 225 plasma concentrations from 96 patients using nonlinear mixed-effects (NLME) modeling in Phoenix NLME software. A retrospective cohort of 52 AML patients receiving VEN with hypomethylating agents was analyzed, grouped as newly diagnosed or relapsed/refractory (R/R). Minimal residual disease (MRD) negativity was the primary endpoint. Mann–Whitney U -tests and logistic regression assessed associations between trough concentration (C 0 ) and 6-hour post-dose concentration (C 6 ) levels and MRD status. Results: A one-compartment model best described the pharmacokinetics of VEN. Body surface area (BSA) and the use of triazole drugs significantly influenced apparent clearance (CL/F), while total protein (TP) had a significant impact on apparent volume of distribution (V/F). The final model estimates were: ka = 0.15 h − 1 (fixed), V/F = 124.7 L, CL/F = 4.8 L⋅h − 1 . In both newly diagnosed and R/R AML patients, C 0 and C 6 concentrations were significantly higher in the MRD-negative group than in the MRD-positive group (all p < 0.05). Exposure–response analyses demonstrated a consistent positive association between higher VEN exposure and MRD negativity. Logistic regression further confirmed that both C 0 and C 6 were independent predictors of achieving MRD negativity. Notably, in the R/R cohort, higher C 6 exposure quartiles were significantly associated with increased MRD-negative rates. Conclusion: This study establishes the first real-world population pharmacokinetic model of venetoclax in Chinese pediatric patients and demonstrates a clinically meaningful exposure–response relationship. The positive association between VEN exposure and MRD negativity supports the use of therapeutic drug monitoring and PPK-guided dosing to optimize treatment in pediatric AML.