The Crucial Role of Pharmacogenetic testing in Thiopurine Therapy

Introduction: The Power of Thiopurine Drugs

Thiopurine drugs, including azathioprine, mercaptopurine, and thioguanine, are potent tools in the treatment of autoimmune diseases, inflammatory bowel disease, and acute lymphoblastic leukaemia, as well as in preventing rejection after solid organ transplants. However, their efficacy is closely tied to the activity of two enzymes: thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15). In this article we look at the importance of thiopurine therapy and pharmacogenetic testing and the potential of more cost-effective treatment.

The Role of TPMT and NUDT15 in Thiopurine Metabolism

Thiopurine drugs are inactive prodrugs that must be metabolised into 6-thioguanine nucleotides (6-TGNs) to function. This metabolic route is catalysed primarily by TPMT. However, TPMT activity can be inhibited by common drugs, which can lead to the accumulation of cytotoxic 6-TGN, contributing to excessive myelosuppression, even with standard doses of thiopurine drugs. This makes genetic testing for these variants crucial for optimising thiopurine therapy dosing and reducing the risk of severe side effects. Prior to starting azathioprine treatment, the Food and Drug Administration (FDA) advises prescribers to take into account genetic or activity testing for TPMT deficiency and to closely monitor treatment using complete blood counts (CBCs).

Monitoring and Testing: A Proactive Approach

Genetic testing can be conducted before or during thiopurine therapy to identify TPMT and NUDT15 variations. TPMT’s enzyme activity phenotype can be directly tested before administering the medication. Following the commencement of treatment, levels of thiopurines and their metabolites can be assessed in order to enhance the accuracy of dosing for thiopurine therapy. However, current practices vary significantly among various specialties, presenting significant challenges to the implementation of testing and the dissemination of results.

Veteran Population Testing in the US

In the United States, the Department of Veterans Affairs (VA) represents the largest healthcare system. However, a significant event in 2014 highlighted the need for more rigorous testing and monitoring of patients prescribed thiopurine drugs. A potential adverse reaction to azathioprine led to the death of a Veteran. This incident, therefore, highlighted the gaps in testing and reliable documentation of pharmacogenetic (PGx) tests in the VA electronic health records (EHRs). Consequently, the VA initiated a risk-reduction programme in 2019. The aim of this initiative is to ensure that medical practitioners monitor patients as per manufacturer recommendations and practice guidelines.

The Cost-Saving Potential of Genetic Testing

Genetic tests for TPMT and NUDT15 variants can potentially save significant costs in treating diseases like leukaemia and organ transplants. These tests can help identify patients at risk of severe side effects from thiopurine drugs. This knowledge allows healthcare providers to adjust dosages or consider other treatment options. This strategy can reduce the occurrence of adverse drug reactions and related healthcare costs. Moreover, a proactive testing and monitoring approach, backed by integrated EHR systems, can prevent adverse drug-use events. This prevention leads to improved patient outcomes and additional cost savings. 

Conclusion: A Call for Proactive Healthcare

The current approach to treating patients with potentially decreased TPMT activity, which is predominantly reactive, has shown its limitations. There is a pressing need for a shift towards a more proactive model of healthcare, where genetic testing for TPMT and NUDT15 variants is standard practice. We need to shift towards a more proactive healthcare model. This model should standardise genetic testing for TPMT and NUDT15 variants. This approach can improve patient outcomes by lowering the risk of severe side effects. It can also lead to significant cost savings in treating diseases like leukaemia and organ transplants. Healthcare providers need to integrate decision supports and clinical dashboards into EHR systems. This will keep them informed about testing needs and available genetic information. This information can guide therapeutic decisions, leading to safer, more effective, and more affordable patient care.