TPMT

TPMT, also known as Thiopurine S-methyltransferase, is an enzyme that determines the level of 6-MMP as well as 6-TGN which are metabolites that are responsible for the potential toxicity and therapeutic aspect of thiopurine medications such as 6-MP, Azathioprine, and Imuran. There is a blood test to check your genetics or the activity level of the enzyme that helps determine if a patient might develop severe side effects or respond poorly to normal dosages of medication. In addition, it has been shown that monitoring TPMT allows for a faster response (22.4 wk vs 18.9 wk) and decreased cost of administration at 1 year ($7142 vs $3861).[5]

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TPMT Enzyme Levels

If you have normal levels of TPMT, your doctor will likely prescribe a normal dose of medication.

If you have low to intermediate (thus you're heterozygous) levels of TPMT, the doctor may prescribe a lower than normal dose of medication. The problem here is heterozygous means you have lower levels of 6-TGN (which you want high levels of) and higher levels of 6-MMP which you want lower levels of. Thus achieving complete remission without side effects is difficult.[5]

If you have little or no TPMT, then you are at extreme risk of side effects such as myelosuppression and thiopurines should not be prescribed.

Some people have high levels of TPMT but it has not yet been determined how this affects thiopurine metabolism.

Notes About TPMT Testing

  • While this test is a good indicator for predicting toxicity, it is not 100% reliable. One study of people with Crohn's Disease who took Azathioprine showcased that, of those with severe side effects, only 27% had mutant genes meaning 73% incurred myelosuppression for other reasons and the TPMT test would not have predicted this.[2] Thus, it is imperative that blood counts be regular tested when taking thiopurine drugs.
  • Use of thiopurines will affect the results of TPMT enzyme testing. The test should be conducted PRIOR to commencing use of the drug.
  • If you have recently had a blood transfusion, TPMT testing could be negatively affected as the test checks enzymes within red blood cells.
  • It has been determine that TPMT testing is a cost effective use of health care resources.[3]

The Genetics of TPMT


Two genes determine how much TPMT enzyme you produce. Most people have two genes that correlate with normal production of TPMT.

Heterozygous means that you produce an intermediate amount of TPMT because you have one normal gene and one gene that causes decreased levels of TPMT. About 1 in 10 people fall within this group. Studies have shown those who are heterozygous are at increased risk of specifically developing leukopenia [1] and 30-60% will develop myelosuppression if a standard dose is given.[4]

If you do not produce any or very little TPMT, that is because you have two genes that produce no TPMT. About 1 in 300 people fit within this group and you are "homozygous".

Independent Group Guidelines


The Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines
  • Heterozygous TPMT genotype (intermediate activity): The initial dose of AZA or 6-MP should be reduced by 30-70%. The AZA dose can be titrated as tolerated. The 6-MP dose should be adjusted based on the severity of myelosuppression and disease-specific guidelines.
  • Homozygous TPMT genotype (variant mutant, low, or deficient activity): Reduce the initial dose of AZA, 6-MP or TG by 10-fold and extend the dosing frequency from daily to three times weekly, or select an alternative drug.
The Royal Dutch Association for the Advancement of Pharmacy Pharmacogenomic Working Group
  • Patients who are intermediate metabolizers based on the TPMT genotype or phenotype test: The dose of AZA or 6-MP should be reduced by 50% and titrated based on hematologic monitoring and efficacy, or select an alternative drug.
  • Patients who are poor metabolizers based on the TPMT genotype or phenotype test: The dose of AZA or 6-MP should be reduced by 90% and titrated based on hematologic monitoring and efficacy, or select an alternative drug.

References


Popular Threads Discussing TPMT



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