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

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 <5700 pmol/8 × 108 RBC and 6-TGN between 230 and 450 pmol/8 × 108 RBC).

RESULTS: The popPK model revealed a linear correlation between 6-MP dose and metabolite concentrations. Allopurinol co-administration substantially shifted metabolites' distribution from 80% 6-MMP/20% 6-TGN to 21% 6-MMP/79% 6-TGN. Simulations identified optimal 6-MP doses of 40-75 mg/m2 without allopurinol, and only 10-15 mg/m2 when co-administered.

CONCLUSION: Allopurinol co-treatment reduces toxicity while maintaining therapeutic efficacy at lower 6-MP doses. The proposed model warrants prospective evaluation for clinical relevance confirmation.