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Thiopurines like azathioprine remain cornerstones for managing autoimmune and inflammatory conditions in India. However, these medications carry a significant risk of severe adverse effects, particularly life-threatening myelosuppression. For this reason, thiopurine toxicity monitoring has become a critical component of modern clinical practice. By understanding a patient's genetic and metabolic profile, clinicians can significantly improve safety and treatment outcomes.
Modern management strategies now advocate for an integrated triple approach. This includes TPMT phenotyping, NUDT15 genotyping, and therapeutic drug monitoring (TDM). In Indian populations, NUDT15 polymorphisms are often more prevalent than TPMT variants. Therefore, relying solely on TPMT testing might miss many high-risk individuals. The NUDT15 c.415C>T (p.R139C) polymorphism, in particular, strongly predicts early leukopenia and hair loss.
Moreover, measuring 6-thioguanine nucleotides (6-TGN) through TDM allows for precise dose adjustments. This ensures that patients receive enough drug for efficacy while avoiding toxic concentrations. Consequently, a recent case series of four Indian patients illustrates that preemptive screening and continuous monitoring prevent bone marrow suppression. Furthermore, these tools help clinicians navigate complex cases involving metabolic shunting or non-compliance. By integrating these methods, doctors can ensure optimal clinical efficacy for every patient.
NUDT15 variants are significantly more common in Asian and Indian populations compared to Western populations. These genetic polymorphisms are strong predictors of severe thiopurine-induced myelosuppression and alopecia, even when TPMT levels are normal.
Monitoring 6-thioguanine nucleotides (6-TGN) helps clinicians assess the actual exposure to the active drug metabolite. This allows for individualized dosing to maintain therapeutic levels while preventing toxic accumulation that leads to bone marrow suppression.
Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice or a professional relationship. Always consult a qualified healthcare provider for diagnosis and treatment. Refer to the latest local and national guidelines for clinical practice.
References
Joseph S et al. An integrated triple approach - TPMT phenotype, NUDT-15 genotype, and therapeutic drug monitoring of thiopurine metabolites for optimal clinical efficacy: a case series. Per Med. 2026 Apr 13. doi: 10.1080/17410541.2026.2657977. PMID: 41969197.
Relling MV, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105(5):1095-1105.
Shah SA, et al. Nucleoside diphosphate-linked moiety X-type motif 15 C415T variant as a predictor for thiopurine-induced toxicity in Indian patients. J Gastroenterol Hepatol. 2017;32(3):620-624.
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