Model‐Based Strategy for 6‐Mercaptopurine Treatment in Acute Lymphoblastic Leukemia Maintenance Phase: Prediction of 6‐TGN and 6‐MMP Concentrations to Optimize Treatment

ABSTRACT Introduction Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The pro‐drug 6‐mercaptopurine (6‐MP), essential during maintenance, is converted into active 6‐thioguanine (6‐TGN) and toxic 6‐methylmercaptopurine (6‐MMP) metabolites, resulting in marked variability in efficacy and toxicity. 6‐MP therapy is further limited by poor adherence, variable absorption, and complex metabolism. Allopurinol is sometimes used to correct skewed metabolism, though its precise clinical role remains unclear. Methods This study aimed to develop population pharmacokinetic (popPK)‐based strategies to optimize 6‐MP dosing in children and improve therapeutic outcomes. A popPK model was developed using 6‐MMP and 6‐TGN concentrations from the pediatric oncology cohort. Model‐based simulations in 1000 virtual patients were performed to explore optimized dosing strategies, with and without allopurinol, aiming to reach the therapeutic target (6‐MMP