Let's get personal: predicting thiopurine and fluoropyrimidine toxicity

Area of Science:

• Pharmacogenomics
• Clinical Pharmacology
• Drug Metabolism

Background:

• The US FDA emphasizes personalized medicine using biomarkers to predict drug response.
• Thiopurine S-methyltransferase (TPMT) testing is established for individualizing azathioprine and mercaptopurine doses.
• Drug metabolite monitoring further refines thiopurine therapy personalization.

Purpose of the Study:

• To summarize research on interindividual differences in thiopurine and fluoropyrimidine drug metabolism.
• To explore factors influencing the clinical adoption of pharmacogenetic testing for these drug classes.

Main Methods:

• Review of recent research on genetic variations affecting thiopurine and fluoropyrimidine metabolism.
• Analysis of clinical practice guidelines and research on pharmacogenetic test implementation.
• Exploration of attitudes and barriers impacting the uptake of Dihydropyrimidine Dehydrogenase (DPD) testing.

Main Results:

• Genetic variations in TPMT and DPD predict severe toxicity for thiopurine and fluoropyrimidine drugs, respectively.
• TPMT testing is integrated into routine clinical practice for dose adjustment.
• DPD testing, despite similar predictive value for fluoropyrimidine toxicity, has not achieved widespread clinical adoption.

Conclusions:

• Parallels exist between TPMT and DPD deficiencies in causing drug toxicity, yet their clinical implementation differs significantly.
• Barriers to pharmacogenetic testing adoption, particularly for DPD, require further investigation and strategic intervention.
• Personalized medicine approaches using pharmacogenetics hold promise but face challenges in translation to routine care.