Cost-effectiveness of TPMT Pharmacogenetics

Conditions

Crohn Disease, Inflammatory Bowel Diseases, Ulcerative Colitis

Keywords

Pharmacogenetics, Cost Effectiveness, Inflammatory Bowel Diseases, Crohn Disease, Ulcerative Colitis, Randomized Controlled Trials

Brief summary

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.

Detailed description

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.

Wong DR, Coenen MJ, Derijks LJ, Vermeulen SH, van Marrewijk CJ, Klungel OH, Scheffer H, Franke B, Guchelaar HJ, de Jong DJ, Engels LG, Verbeek AL, Hooymans PM, TOPIC Recruitment Team.

2016-12-1234 citations

10.1111/apt.13879

Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease.

Wong DR, Coenen MJ, Vermeulen SH, Derijks LJ, van Marrewijk CJ, Klungel OH, Scheffer H, Franke B, Guchelaar HJ, de Jong DJ, Engels LG, Verbeek AL, Hooymans PM, TOPIC recruitment team.

2016-07-0945 citations

10.1093/ecco-jcc/jjw130

Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease.

Coenen MJ, de Jong DJ, van Marrewijk CJ, Derijks LJ, Vermeulen SH, Wong DR, Klungel OH, Verbeek AL, Hooymans PM, Peters WH, te Morsche RH, Newman WG, Scheffer H, Guchelaar HJ, Franke B, TOPIC Recruitment Team.

2015-06-11150 citations

10.1053/j.gastro.2015.06.002

Oral Session III

Marieke J. H. Coenen, Corine van Marrewijk, Luc J. J. Derijks, Sita H. Vermeulen, Danny Wong et al. (14 authors)

Clinical Pharmacology & Therapeutics2015-01-22

10.1002/cpt.56

OP006 Personalized thiopurine dosing based on TPMT genotyping reduces leucopenia occurrence and results in cost-savings in IBD patients. Results from a randomized trial in the Netherlands

Marieke J. H. Coenen, Corine van Marrewijk, L. Derijks, Sita H. Vermeulen, Dennis R. Wong et al. (12 authors)

Journal of Crohn s and Colitis2014-02-013 citations

10.1016/s1873-9946(14)60007-6

Interventions

GENETICTPMT 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;

DRUGazathioprine (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);

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SUPPORTIVE_CARE

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

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

Design outcomes

Primary

Measure	Time frame
Haematological adverse drug reactions	0-5 months

Secondary

Measure	Time frame
TPMT enzym activity	at baseline
Therapeutic Drug Monitoring of TPMT Metabolites	week 1 and 8
Health related quality of life	5 months
Treatment compliance	0 to 5 months
Non-haematological Adverse Drug Reactions	0- 5 months
Clinical outcome (disease activity)	5 months
Cost-efficacy	5 months

Countries

Netherlands

Outcome results

None listed