Thiopurine Dosing Guideline in Immunosuppressive Therapy

1 in 200 individuals (0.5%) have severe TPMT deficiency which results in rapid life-threatening myelosuppression, usually within 7 to 10 days of initiating treatment.

Definitions

• Thiopurines: a class of drugs used to suppress the normal activity of the body’s immune system, and includes azathioprine, 6-mercaptopurine, and 6-thioguanine. These are all prodrugs.
• TPMT: Thiopurine methyltransferase (a key enzyme in the metabolism of thiopurines)
• 6TGN: 6-thioguanine nucleotide (active metabolite)
• 6MMP: 6-methyl-mercaptourine (active toxic metabolite)

Thiopurine Methyltransferase (TPMT)

• Key steps in the metabolism of thiopurines:
  • Azathioprine is metabolised in the liver to 6-mercaptopurine by glutathione S-transferase.
  • 6-mercaptopurine is metabolised to 6MMP by TPMT
  • 6-thioguanine is metabolised to 6TGN by TPMT
• TPMT polymorphisms result in large differences in 6TGN and 6MMP concentrations, so it is important to measure TPMT enzyme activity (i.e. phenotype) before initiating thiopurine therapy.
• In adult patients with normal TPMT enzyme activity the usual target dose are:
  • azathioprine = 2 to 3 mg/kg/day
  • 6-mercaptopurine = 1 to 1.5 mg/kg/day
  • 6-thioguanine = approximately 0.3/kg/day
• In patients with intermediate TPMT deficiency (approximately 10% of the population) give 30 to 50% of the normal target dose.
• In patients with severe deficiency (where TPMT may be very low or absent) give 10% of the normal target dose.
• If initiation of therapy is urgent and TPMT enzyme activity is unknown, initiate on 30 to 50% of usual dose and check enzyme activity within the first week.
• If originally initiated on treatment without knowing the TPMT enzyme activity:
  • Check enzyme activity as soon as possible.
  • Reduce the dose depending on severity of deficiency, discuss with a relevant specialist (Clinical Pharmacology, Gastroenterology) and monitor closely.

Other Monitoring

• Monitoring of complete blood count (CBC) and liver function is required weekly for 4 weeks on initiation of treatment, in view of the high rate of myelosuppression and hepatotoxicity. After 4 weeks monitoring can be monthly for 3 months, and then 3-monthly thereafter.
• Monitoring may need to be more frequent if there are deficiencies in enzyme activity.

6-TGN and 6-MMP Monitoring

• Monitoring of 6-TGN and 6-MMP should occur at 4 weeks (steady state) after treatment initiation, or after a dose change.
• When treating inflammatory bowel disease with 6-mercaptopurine or azathioprine, aim for concentrations of the active 6-TGN to be in the therapeutic range of 235-450 picomol/8x10⁸ RBC. This might be used as a guide in other conditions. If treating with 6-thioguanine, the target therapeutic range is 800-1200 picomol/ 8x10⁸ RBC.
• Concentrations of 6-TGN > 450 picomol/8x10⁸ RBC have been associated with myelosuppression, when using azathioprine or 6-MP.
• Concentrations of 6-MMP > 5,700 picomol/8x10⁸ RBC have been associated with hepatotoxicity.
• If the concentration of 6-MMP is > 20 times that of 6-TGN, consult with Clinical Pharmacology. It may be possible to improve drug response and reduce toxicity by adding allopurinol 100 mg, but only with a dose reduction of the thiopurine to one-third (e.g. 150 mg down to 50 mg).

Topic Code: 191833

must be prescribed or recommended by a consultant.