Thiopurines in IBD
Indications:
• Steroid-sparing agents indicated for maintenance of remission in UC and CD
• Not induction agents. Slow onset of action (~12 weeks)
• In combination with aTNF -> increase aTNF levels and decrease Ab formation -> better outcomes
Metabolism:
• Thiopurine S-methyltransferase (TPMT)
• 6-TGN: active metabolite. Associated to drug efficacy and Bone Marrow toxicity
• 6-MMP: inactive metabolite. Associated to Hepatotoxicity
• "Shunters" or "Hypermethylators": preferentially metabolyze 6MP towards 6-MMP
Dosage:
• Based on TPMT activity. NUDT15 gene mutations associated to leukopenia (Asian populations)
• Homozygous low activity: avoid thiopurines. Highest risk for severe and fatal myelosupression
• Heterozygous or intermediate activity: decrease dose by 50%
• Homozygous high or normal activity: AZA 2-3mg/kg and MP 1-1.5mg/kg
TDM (thiopurine metabolites):
• 4 to 6 weeks after start and after dose changes/allopurinol addition
• Reactive
• when determination of compliance is needed
• 6TG 235-450 associated to good clinical response.
- low 6TG/low 6MMP: increase dose by 25-50mg.
- low 6TG/high 6MMP ("shunter"): decrease dose by 25% and add allopurinol 100mg qd or
dose splitting
- Absent or minimal 6TG and 6MMP: non-compliant.
- High 6TG and not responding:
- switch MOA. 6TG> 125 may be adequate to achieve good levels of IFX.
Safety:
• Serious Infections: lower rate when compared to aTNF. (*But less effective drugs). GI intolerance. Pancreatitis (dose-independent, 3%)
• Bone marrow toxicity: linked to high 6TG>400. Monitor CBC q 1-2 weeks initially and then q3m
• Hepatotoxicity: linked to high 6MMP > 5700
• NMSC. Lymphomas are ↑ but uncommon (>aTNF). Risk becomes ↑ after 1y of exposure. Absolute risk ↑ > 50yo. HSTC lymphoma (potentially fatal): men < 35 yo on Rx > 2y are at ↑ risk. EBV seroconversion is a concern-most adults already EBV+
Dr. Jean Donet @JeanDonet
#Thiopurines #IBD #Inflammatory #BowelDisease #Management #Treatment
