Cost-effectiveness of TPMT Pharmacogenetics (TOPIC)

• (Haematological) Adverse Drug Reactions [ Time Frame: 1, 2, 4, 6, 8 weeks and 5 months ] [ Designated as safety issue: Yes ]
• Clinical outcome (disease activity) [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• Treatment compliance [ Time Frame: 0 to 5 months ] [ Designated as safety issue: No ]
• TPMT enzym activity [ Time Frame: at baseline ] [ Designated as safety issue: No ]
• Therapeutic Drug Monitoring of TPMT Metabolites [ Time Frame: week 1 and 8 ] [ Designated as safety issue: No ]
• Health related quality of life [ Time Frame: 5 months ] [ Designated as safety issue: No ]

• (Haematological) Adverse Drug Reactions [ Time Frame: 1, 2, 4, 6, 8 weeks and 5 months ]
• Clinical outcome (disease activity) [ Time Frame: 5 months ]
• Health related quality of life [ Time Frame: 5 months ]
• Treatment compliance [ Time Frame: 0 to 5 months ]

The purpose of this study is to determine whether thiopurine S-methyltransferase (TPMT) genotyping prior to thiopurine use is cost-effective in patients with inflammatory bowel disease (IBD) in need of immune suppression.

The study is designed to test the hypothesis that optimization of initial thiopurine dose based on pre-treatment TPMT genotyping will maximize treatment efficacy and minimize adverse drug reactions (ADRs) resulting in reduced costs.

Immunosuppressives, e.g. azathioprine (AZA) and 6-mercaptopurine (6-MP), are important in induction of remission and long term treatment of (ulcerative) colitis and Crohn's disease when treatment with 5-aminosalicylates and corticosteroids fails. ADRs to immunosuppressive treatment, including myelosuppression and hepatotoxicity, are frequently (15-30%) observed. Genetic variation in the TPMT gene results in 10-11% of the general population in reduced and in 0.3-0.6% to negligible TPMT enzyme activity. In IBD patients, this genetic variation predicts 25-40% of the haematological ADRs necessitating tempering of thiopurine dose or discontinuation of treatment.

Pharmacogenetics aims at providing optimized drug treatment to patients by maximizing efficacy and minimizing adverse drug reactions (ADRs) based on genetic testing. Despite the proven value of pharmacogenetics in clinical practice, its use in medical care is still limited.

The best-established example of a pharmacogenetic test is genotyping of thiopurine S-methyltransferase (TPMT) in the treatment of patients with immunosuppressive thiopurines. Nonetheless, it is not used on a large scale in clinical practice so far, which might be due to: insufficient information transfer from research to clinic; lack of cost-effectiveness analyses (CEAs); lack of availability of (or access to) fast and/or cheap genotyping; or lack of test reimbursement by health insurance.

• Inflammatory Bowel Diseases
• Crohn Disease
• Ulcerative Colitis

• Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine

  Assessment of the polymorphisms G238C, G460A, and A719G in a venous blood sample to identify functional genetic variants (TPMT*2, *3A, *3C) of the TPMT gene (chromosome 6) associated with reduced or negligible TPMT enzyme activity.

  Patients are advised an initial treatment dose based on the enzyme activity:

  • Normal: AZA 2-2.5 mg/kg/day or 6-MP 1-1.5 mg/kg/day (standard care);
  • Reduced: AZA 1-1.25 mg/kg/day or 6-MP 0.5-0.75 mg/kg/day;
  • Negligible: AZA 0-0.2 mg/kg/day or 6-MP 0-0.1 mg/kg/day;
  Other Names:

  • Imuran
  • Puri-Nethol
• Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

  Patients will be advised a standard initial treatment dose:

  • AZA 2-2.5 mg/kg/day or 6-MP 1-1.5 mg/kg/day (standard care);
  Other Names:

  • Imuran
  • Puri-Nethol

• Experimental: Intervention, TPMT genotyping
  Pre-treatment TPMT genotyping to optimize initial thiopurine treatment dose. Intervention is based on the genotype.
  Intervention: Genetic: TPMT genotyping; Drug: azathioprine or 6-mercaptopurine
• Active Comparator: control
  Standard thiopurine treatment
  Intervention: Drug: azathioprine (AZA) or 6-mercaptopurine (6-MP)

Inclusion Criteria:

• Age 18 or older
• Diagnosis of a form of IBD
• Indication for azathioprine/6-MP treatment
• Patient giving (written) informed consent

Exclusion Criteria:

• Previous treatment with azathioprine/6-MP
• Co-prescription of allopurinol (this treatment blocks xanthine oxidase, an enzyme important for thiopurine metabolism)
• Baseline leukocyte count less then 3x10^9 per litre
• Reduced liver function at baseline
• Reduced renal function at baseline
• Known TPMT phenotype (enzyme activity / Therapeutic Drug Monitoring) or genotype
• Pregnancy or breastfeeding