Tioguanine (thioguanine)

Tioguanine (also called thioguanine) is a thiopurine drug used in low dose as an alternative to azathioprine and mercaptopurine (both thiopurines) as an immune suppressant. It is used in the treatment of inflammatory bowel disease (IBD) and autoimmune hepatitis. It was developed initially for cancer treatment and is used in acute leukaemia and chronic myeloid leukaemia. However, the following guidance applies to use in IBD.

 

Indications for measuring +
  • To guide dose-adjustment towards optimal drug exposure in relation to drug efficacy and toxicity.
    • Therapeutic drug monitoring of 6-thioguanine nucleotides (6-TGN) is recommended in IBD patients on tioguanine.
  • Diagnosis
    • Differentiating disease resistant to drug versus inadequate drug exposure (including uncertain adherence)
    • Differentiating adverse drug reaction versus underlying disease

How to measure

Assay detail

See Canterbury Health Labs 6-TGN assay information.

Timing of concentration sample collection

  • Blood samples for 6-TGN monitoring can be taken at any time in relation to the dose because of the long half-lives of these metabolites.
  • Concentrations of 6-TGN should be checked at least 4 weeks after commencing drug or changing dose as the tioguanine and 6-TGN half-lives are around 5 days.
  • The turnaround time of 6-TGN concentrations is usually less than 7 days.

Alternatives to monitoring concentration

  • Clinicians are encouraged to consider additional gauges of drug effect dependent on clinical presentation and other blood tests (see below).

Other Monitoring

  • TPMT (thiopurine methyltransferase) is a key enzyme in the metabolism of thiopurines. TPMT polymorphisms result in large differences in 6-TGN concentrations, which can be life-threatening, so it is important to measure TPMT enzyme activity before initiating thiopurine therapy.
  • Measure NUDT15 (nudix hydrolase) genotype in Asian patients before initiating thiopurine therapy, as polymorphisms for this enzyme result in severe toxicity,
  • Full blood count and liver function tests (AST, ALT, ALP, GGT) should be monitored at 1, 2, 3, 4, 8, 12 and 16 weeks after starting tioguanine; then every 3 months thereafter.
  • Note: 6-methyl-mercaptopurine (6-MMP) is not routinely measured in patients on tioguanine (unlike in patients on azathioprine and mercaptopurine) as it is usually undetectable.

How to interpret

Reference Range 

Interpretation 6-TGN
Under-dosing or poor compliance < 800 pmol/8 x108 RBC
Adequate dosing 800–1,200 pmol/8 x108 RBC*
Potential Toxicity > 1200 pmol/8 x108 RBC
*Note Canterbury Health Lab reference range is 235–450 pmol/8 x108 RBC is for azathioprine and mercaptopurine and does not apply to tioguanine use.

Factors affecting interpretation

Factors that may give a false assay result

  • Blood transfusion within 3 months can affect TPMT enzyme activity result. Monitor for myelosuppression weekly and repeat TPMT enzyme activity test 3 months following the last transfusion.

Dose individualisation and adjustment

  • In adults with normal TPMT enzyme activity, the initial dosing in IBD is 0.3 mg/kg/day not exceeding 25 mg/day in adults.
  • In patients with intermediate TPMT enzyme activity start at 33 to 50% of usual dose. Consider three times per week dosing.
  • In patients with low/absent TPMT enzyme activity start at 10% of usual dose. Alternate day, or three times per week dosing, is recommended.
  • 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.
  • Consider using a reduced initial dose in elderly patients or those with impaired renal or hepatic function.
  • Adjust dose according to 6-TGN concentrations; aiming for a concentration between 800–1,200 pmol/8 x108 RBC.
  • Dose adjustment may result in dosing outside of that which is Medsafe-approved.

Other dosing considerations

  • Initial dosing is usually 20 mg/day. Tablets will need to be halved or can be given on alternate days depending on patient preference.
    • Dosing of 10 mg/day can be given as 20 mg on alternative days.
    • Dosing of 30 mg/day can be given as 20 mg and 40 mg on alternate days.
    • Dosing of 40 mg per day should be given as 20 mg twice daily to reduce risk of liver toxicity.

Contacts for help with interpretation

Medicines Information: phone 03 364 0900 or email medicines.information@cdhb.health.nz

Key References

Khan A, Berahmana AB, Day AS, et al. New Zealand Society of Gastroenterology Guidelines on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. N Z Med J. 2019;132(1491):46-62

Crouwel F, Simsek M, Mulder CJ, et al. Thioguanine Therapy in Inflammatory Bowel Diseases. A Practical Guide. J Gastrointestin Liver Dis. 2020;29(4):637-45

Derijks LJ, Gilissen, LP, Engels LG, et al. Pharmacokinetics of 6-Thioguanine in Patients With Inflammatory Bowel Disease. Therapeutic Drug Monitoring 2006;28(1):45-50

Thiopurine Dosing Guideline in Immunosuppressive Therapy 2020. Available in: Preferred Medicines List – the Pink Book

Last updated

February 2024