Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-based Drugs: Evidence Report/Technology As (en Inglés)
Reseña del libro "Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-based Drugs: Evidence Report/Technology As (en Inglés)"
Thiopurine drugs are used to treat chronic autoimmune inflammatory conditions and hematological malignancies, and to prevent organ transplant rejection. The present study focuses on populations with autoimmune disease. Thiopurine drugs are associated with various toxic adverse effects, including myelosuppression, hepatotoxicity, pancreatitis, and flu-like symptoms. The most extensively characterized enzyme in the metabolism of thiopurines is thiopurine methyltransferase (TPMT). TPMT inactivates the active forms of two commonly used thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine (6-MP), by methylation. Multiple studies have shown that lower TPMT enzymatic activity is correlated with higher levels of the active drug metabolites and increased thiopurine toxicity. Genetic polymorphisms associated with lower TPMT enzymatic activity are similarly correlated. Approximately 0.3% of the population with chronic autoimmune disease that could potentially benefit from thiopurine treatment is homozygous for a variant TPMT allele expressed as low or even absent TPMT activity. These patients are at greatest risk of myelosuppression. Various clinical guidelines recommend measuring TPMT enzymatic activity or screening for TPMT alleles before starting patients on thiopurine drugs. However, the evidence base for these recommendations is unclear. As such, there is a need to review the current literature regarding the assessment of TPMT status prior to administration of thiopurine drugs, to determine if pretreatment TPMT testing reduces drug-related toxicity. This report was commissioned by the Agency for Healthcare Research and Quality to address the following of questions about TPMT genotypic and phenotypic testing methodology, their comparative diagnostic accuracy, effectiveness of pretreatment testing, association with drug toxicity, and costs involved.KQ1. In terms of the analytical performance characteristics of enzymatic measurement of TPMT activity and determination of TPMT allelic polymorphisms: a) What are the preanalytical requirements for enzymatic measurement of TPMT and determination of TPMT allelic polymorphisms? b) What are the within and between laboratory precision and reproducibility of the available methods of enzymatic measurement of TPMT and determination of TPMT allelic polymorphisms? c) What is the diagnostic sensitivity and specificity of TPMT allelic polymorphism measurement compared to the measurement of TPMT enzymatic activity in correctly identifying chronic autoimmune disease patients eligible for thiopurine therapy with low or absent TPMT enzymatic activity? How do effect modifiers explain any observed heterogeneity in sensitivity and specificity? d) Are there any postanalytical requirements specific to measurement of TPMT enzymatic activity or TPMT allelic polymorphism measurement? KQ2. Does the measurement of TPMT enzymatic activity or determination of TPMT allelic polymorphisms change the management of patients with chronic autoimmune disease when compared with no determination of TPMT status? KQ3. In chronic autoimmune disease patients prescribed thiopurine-based drugs (AZA or 6-MP), does the assessment of TPMT status to guide therapy, when compared with no pretreatment assessment, lead to: a) reduction in rates of mortality, infection, hospitalization, withdrawal due to adverse events, serious adverse events and improvement in health-related quality of life? b) reduction in rates of myelotoxicity, liver toxicity, and pancreatitis? c) In the absence or inconclusiveness of evidence answering key question 3a and/or 3b above, is there an association between TPMT status and/or the following amongst chronic autoimmune disease patients treated with thiopurines? KQ4. What are the costs of determining TPMT enzyme activity and/or genotyping for patients with chronic autoimmune disease being considered for thiopurine-based therapy?
