Model-Based Strategy for 6-Mercaptopurine Treatment in Acute Lymphoblastic Leukemia Maintenance Phase: Prediction of 6-TGN and 6-MMP Concentrations to Optimize Treatment.
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.
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).
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.
Allopurinol co-treatment reduces toxicity while maintaining therapeutic efficacy at lower 6-MP doses. The proposed model warrants prospective evaluation for clinical relevance confirmation.
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).
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.
Allopurinol co-treatment reduces toxicity while maintaining therapeutic efficacy at lower 6-MP doses. The proposed model warrants prospective evaluation for clinical relevance confirmation.
Authors
Ravix Ravix, Maillat Maillat, Choong Choong, Csajka Csajka, Guidi Guidi, Ceppi Ceppi
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