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Avoiding adverse drug reactions by pharmacogenetic testing: A systematic review of the economic evidence in the case of TPMT and AZA-induced side effects

  • Amelia Compagni (a1), Simona Bartoli (a1), Bernhard Buehrlen (a2), Giovanni Fattore (a1), Dolores Ibarreta (a3) and Emma Gutierrez de Mesa (a4)...


Objectives: The study aims at evaluating the economic evidence related to testing for genetic variants of the drug-metabolizing enzyme, TPMT. Detecting TPMT genetic variants before the administration of azathioprine (AZA) has the potential to prevent serious and costly adverse drug reactions (ADRs), such as neutropenia. In particular, our analysis concentrated on assessing the reliability of data on costs of neutropenia and performing the tests, the two main cost categories that could inform an economic evaluation of TPMT pharmacogenetic testing.

Methods: A systematic literature review was performed to gather evidence on the costs of testing and neutropenia. Articles were critically appraised for their comprehensiveness and quality. To better estimate costs of TPMT tests, a small-scale survey of European diagnostic laboratories was conducted.

Results: Only seven articles were retrieved specifying the costs associated with the management and treatment of AZA-induced neutropenia. Most of these studies are based on theoretical modeling reconstructed with key-informants or on very few cases of ADRs, and either the methodology for cost calculation is not specified or costs are based on national cost databases and tariffs. After critical appraisal of these studies, we considered €2,116 as the most reliable estimate for the cost of a case of neutropenia. Literature review accompanied by the survey of several diagnostic laboratories also provided an estimate (€68) for TPMT testing. Based on these values, the net cost per prevented case of neutropenia equals to €5,300.

Conclusions: Solid economic considerations related to TPMT pharmacogenetic testing are still limited by underreporting of ADRs and high level of approximation related to cost data. Ad hoc observational studies and the ADR recording process embedded in pharmacovigilance systems, established across Europe, should represent more reliable sources of cost data in the future.



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1. Colombel, J, Ferrari, N, Debuysere, H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118:10251030.
2. Connell, WR, Kamm, MA, Ritchie, JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34:10811085.
3. Dubinsky, MC, Reyes, E, Ofman, J, et al. A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol. 2005;100:22392247.
4. European Commission. Pharmacogenetics and pharmacogenomics: State-of-the-art and potential socio-economic impact in the EU. EUR22214. Brussels: European Commission; 2006.
5. Flowers, CR, Veenstra, D. The role of cost-effectiveness analysis in the era of pharmacogenomics. Pharmacoeconomics. 2004;22:481493.
6. Gearry, RB, Barclay, ML, Burt, MJ, et al. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol Drug Saf. 2004;13:563567.
7. Gisbert, JP, Gonzalez-Lama, Y, Mate, J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: A systematic review. Am J Gastroenterol. 2007;102:15181527.
8. Haddow, JE, Palomaki, GE. ACCE: A model process for evaluating data on emerging genetic tests. In: Human genome epidemiology: A scientific foundation for using genetic information to improve health and prevent disease. Oxford: Oxford University Press; 2003.
9. Hopkins, MM, Ibarreta, D, Gaisser, S, et al. Putting pharmacogenetics into practice. Nat Biotechnol. 2006;24:403410.
10. Hughes, DA, Pirmohamed, M. Warfarin pharmacogenetics: Economic considerations. Pharmacoeconomics. 2007;25:899902.
11. Lazarou, J, Pomeranz, BH, Corey, PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA. 1998;279:12001205.
12. Marra, CA, Esdaile, JM, Anis, AH. Practical pharmacogenetics: The cost effectiveness of screening for thiopurine s-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol. 2002;29:25072512.
13. Oh, KT, Anis, AH, Bae, SC. Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology (Oxford). 2004;43:156163.
14. Payne, K, Newman, W, Fargher, E, et al. TPMT testing in rheumatology: Any better than routine monitoring? Rheumatology (Oxford). 2007;46:727729.
15. Phillips, KA, Van Bebber, SL. Measuring the value of pharmacogenomics. Nat Rev Drug Discov. 2005;4:500509.
16. Phillips, KA, Veenstra, DL, Oren, E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. JAMA. 2001;286:22702279.
17. Prashker, MJ, Meenan, RF. The total costs of drug therapy for rheumatoid arthritis. A model based on costs of drug, monitoring, and toxicity. Arthritis Rheum. 1995;38:318325.
18. Priest, VL, Begg, EJ, Gardiner, SJ, et al. Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease. Pharmacoeconomics. 2006;24:767781.
19. Robertson, JA, Brody, B, Buchanan, A, et al. Pharmacogenetic challenges for the health care system. Health Aff (Millwood). 2002;21:155167.
20. Sanderson, J, Ansari, A, Marinaki, T, et al. Thiopurine methyltransferase: Should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem. 2004;41:294302.
21. Schutz, E, Gummert, J, Mohr, F, et al. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet. 1993;341:436.
22. Shah, J. Criteria influencing the clinical uptake of pharmacogenomic strategies. BMJ. 2004;328:14821486.
23. Sies, C, Florkowski, C, George, P, et al. Measurement of thiopurine methyl transferase activity guides dose-initiation and prevents toxicity from azathioprine. N Z Med J. 2005;118:U1324.
24. Tavadia, SM, Mydlarski, PR, Reis, MD, et al. Screening for azathioprine toxicity: A pharmacoeconomic analysis based on a target case. J Am Acad Dermatol. 2000;42:628632.
25. Teml, A, Schaeffeler, E, Herrlinger, KR, et al. Thiopurine treatment in inflammatory bowel disease: Clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet. 2007;46:187208.
26. Timmer-Bonte, JN, Adang, EM, Termeer, E, et al. Modeling the cost effectiveness of secondary febrile neutropenia prophylaxis during standard-dose chemotherapy. J Clin Oncol. 2008;26:290296.
27. Van Den Akker-van Marle, ME, Gurwitz, D, Detmar, SB, et al. Cost-effectiveness of pharmacogenomics in clinical practice: A case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe. Pharmacogenomics. 2006;7:783792.
28. Walmsley, TA, Florkowski, CM, George, PM, et al. Thiopurine methyltransferase activity and azathioprine. N Z Med J. 2002;115:302.
29. WHO, Collaborating Center in International Drug Monitoring. Definitions- as adopted by national centers participating in the WHO international drug monitoring program. BMJ. 1992;304:465.
30. Winter, JW, Gaffney, D, Shapiro, D, et al. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2007;25:10691077.
31. Winter, J, Walker, A, Shapiro, D, et al. Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2004;20:593599.
32. Wolf, CR, Smith, G, Smith, RL. Science, medicine, and the future: Pharmacogenetics. BMJ. 2000;320:987990.


Avoiding adverse drug reactions by pharmacogenetic testing: A systematic review of the economic evidence in the case of TPMT and AZA-induced side effects

  • Amelia Compagni (a1), Simona Bartoli (a1), Bernhard Buehrlen (a2), Giovanni Fattore (a1), Dolores Ibarreta (a3) and Emma Gutierrez de Mesa (a4)...


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