WORLD JOURNAL OF ADVANCE
HEALTHCARE RESEARCH

Mrs. Jayalakshmi Venugopal*, Dr. M. P. Amshaja, Mr. Mugilan G., Mr. Mohammed Nawaz Abrar P. N., Ms. Monisha J.

ABSTRACT

Mercaptopurine (6 MP) is a key component of maintenance therapy for acute lymphoblastic leukemia, but optimizing its dose is challenging due to large differences between patients in how the drug is metabolized and how they respond. This review discusses the pharmacometric models used to support 6 MP dosing, with a focus on population pharmacokinetic (PopPK) approaches that describe the kinetics of its active metabolites—6 thioguanine nucleotides (6 TGNs) and 6 methylmercaptopurine nucleotides (6 mMPNs).The article outlines how 6 MP is processed through competing enzymatic pathways, chiefly involving thiopurine S methyltransferase (TPMT) and NUDT15, producing metabolites that drive both therapeutic benefit and toxicity. PopPK models based on nonlinear mixed effects methods have allowed researchers to estimate clearance parameters, explain inter patient variability, and include patient specific covariates such as age, weight, and genotype. Regression based extensions of these models provide a more refined way to capture the drug’s nonlinear kinetics and complex covariate effect relationships.A major challenge emphasized in the review is the impact of TPMT and NUDT15 genetic polymorphisms, which differ widely across populations—especially in Asian and Indian cohorts—and strongly influence the risk of myelosuppression and hepatotoxicity. The difficulty of measuring intracellular 6 TGN concentrations, along with the long duration of maintenance therapy and ongoing changes in patient physiology, further hinders accurate dose individualization.The article concludes that building out pharmacogenomic testing capacity, developing population specific pharmacometric models that reflect local allele frequencies, and integrating model informed precision dosing (MIPD) with Bayesian updating are crucial steps toward achieving safer and more effective 6 MP therapy in the management of leukemia.

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