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Thiopurine S-Methyltranferase Testing in Idiopathic Pulmonary Fibrosis: A Pharmacogenetic Cost-Effectiveness Analysis

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An Erratum to this article was published on 11 April 2011

Abstract

Azathioprine in combination with N-acetylcysteine (NAC) and steroids is a standard therapy for idiopathic pulmonary fibrosis (IPF). Its use, however, is limited by its side effects, principally leukopenia. A genotypic assay, thiopurine S-methyltransferase (TPMT), has been developed that can potentially identify those at risk for developing leukopenia with azathioprine, and thereby limit its toxicity. In those with abnormal TPMT activity, azathioprine can be started at lower dose or an alternate regimen selected. Determine the cost-effectiveness of a treatment strategy using TPMT testing before initiation of azathioprine, NAC, and steroids in IPF by performing a computer-based simulation. We developed a decision analytic model comparing three strategies: azathioprine, NAC and steroids with and without prior TPMT testing, and conservative therapy, consisting of only supportive measures. Prevalence of abnormal TPMT alleles and complication rates of therapy were taken from the literature. We assumed a 12.5% incidence of abnormal TPMT alleles, 4% overall incidence of leukopenia while taking azathioprine, and that azathioprine, NAC, and steroids in combination reduced IPF disease progression by 14% during 12 months. TPMT testing before azathioprine, NAC, and steroids was the most effective and most costly strategy. The marginal cost-effectiveness of the TPMT testing strategy was $49,156 per quality adjusted life year (QALY) gained versus conservative treatment. Compared with azathioprine, NAC and steroids without prior testing, the TPMT testing strategy cost only $29,662 per QALY gained. In sensitivity analyses, when the prevalence of abnormal TPMT alleles was higher than our base case, TPMT was “cost-effective.” At prevalence rates lower than our base case, it was not. TPMT testing before initiating therapy with azathioprine, NAC, and steroids is a cost-effective treatment strategy for IPF.

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References

  1. American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161:646–664

    Google Scholar 

  2. Walter N, Collard HR, King TE Jr (2006) Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc 3:330–338

    Article  CAS  PubMed  Google Scholar 

  3. Bouros D, Antoniou KM (2005) Current and future therapeutic approaches in idiopathic pulmonary fibrosis. Eur Respir J 26:693–702

    Article  CAS  PubMed  Google Scholar 

  4. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias (2002) Am J Respir Crit Care Med 165:277–304

    Google Scholar 

  5. Raghu G, Brown KK, Bradford WZ et al (2004) A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 350:125–133

    Article  CAS  PubMed  Google Scholar 

  6. Demedts M, Behr J, Buhl R et al (2005) High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353:2229–2242

    Article  CAS  PubMed  Google Scholar 

  7. Nicholson AG, Colby TV, Dubois RM et al (2000) The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 162:2213–2217

    CAS  PubMed  Google Scholar 

  8. Raghu G, Depaso WJ, Cain K et al (1991) Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective, double-blind randomized, placebo-controlled clinical trial. Am Rev Respir Dis 144:291–296

    CAS  PubMed  Google Scholar 

  9. Launay D, Remy-Jardin M, Michon-Pasturel U et al (2006) High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 33:1789–1801

    PubMed  Google Scholar 

  10. Wu A, Fuhlbrigge A (2008) Economic evaluation of pharmacogenetic tests. Clin Pharmacol Ther 84:272–274

    Article  CAS  PubMed  Google Scholar 

  11. Singh A (2007) Pharmacogenomics—the potential of genetically guided prescribing. Aust Fam Physician 36:820–824

    PubMed  Google Scholar 

  12. Mallal S, Phillips E, Carosi G et al (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358:568–579

    Article  PubMed  Google Scholar 

  13. Sanderson S, Emery J, Higgins J (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 7:97–104

    Article  CAS  PubMed  Google Scholar 

  14. Schalekamp T, Brasse BP, Roijers JF et al (2006) VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects over-anticoagulation. Clin Pharmacol Ther 80:13–22

    Article  CAS  PubMed  Google Scholar 

  15. Eichelbaum M, Fromm MF, Schwab M (2004) Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit 26:180–185

    Article  CAS  PubMed  Google Scholar 

  16. Ingelman-Sundberg M (2008) Pharmacogenomic biomarkers for prediction of severe adverse drug reactions. N Engl J Med 358:637–639

    Article  CAS  PubMed  Google Scholar 

  17. Perri D, Cole DE, Friedman O et al (2007) Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase. Eur Respir J 30:1014–1017

    Article  CAS  PubMed  Google Scholar 

  18. Flowers JR, Clunie G, Burke M et al (1992) Bronchiolitis obliterans organizing pneumonia: the clinical and radiological features of seven cases and a review of the literature. Clin Radiol 45:371–377

    Article  CAS  PubMed  Google Scholar 

  19. Ansari A, Hassan C, Duley J et al (2002) Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 16:1743–1750

    Article  CAS  PubMed  Google Scholar 

  20. Schwab M, Schaffeler E, Marx C et al (2002) Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics 12:429–436

    Article  CAS  PubMed  Google Scholar 

  21. Gisbert JP, Gomollon F, Cara C et al (2007) Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Dig Dis Sci 52:1262–1269

    Article  CAS  PubMed  Google Scholar 

  22. Kroplin T, Weyer N, Gutsche S et al (1998) Thiopurine S-methyltransferase activity in human erythrocytes: a new HPLC method using 6-thioguanine as substrate. Eur J Clin Pharmacol 54:265–271

    Article  CAS  PubMed  Google Scholar 

  23. Kroplin T, Weyer N, Iven H (1998) Determination of thiopurine methyltransferase activity in erythrocytes using 6-thioguanine as the substrate. Adv Exp Med Biol 431:741–745

    CAS  PubMed  Google Scholar 

  24. Meggitt SJ, Reynolds NJ (2001) Azathioprine for atopic dermatitis. Clin Exp Dermatol 26:369–375

    Article  CAS  PubMed  Google Scholar 

  25. Winter J, Walker A, Shapiro D et al (2004) Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment Pharmacol Ther 20:593–599

    Article  CAS  PubMed  Google Scholar 

  26. Oh KT, Anis AH, Bae SC (2004) Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology (Oxford) 43:156–163

    Article  CAS  Google Scholar 

  27. Fargher EA, Eddy C, Newman W et al (2007) Patients’ and healthcare professionals’ views on pharmacogenetic testing and its future delivery in the NHS. Pharmacogenomics 8:1511–1519

    Article  PubMed  Google Scholar 

  28. McLeod HL, Siva C (2002) The thiopurine S-methyltransferase gene locus—implications for clinical pharmacogenomics. Pharmacogenomics 3:89–98

    Article  CAS  PubMed  Google Scholar 

  29. Yates CR, Krynetski EY, Loennechen T et al (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608–614

    CAS  PubMed  Google Scholar 

  30. Gearry RB, Barclay ML, Burt MJ et al (2003) Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Aliment Pharmacol Ther 18:395–400

    Article  CAS  PubMed  Google Scholar 

  31. Ameyaw MM, Collie-Duguid ES, Powrie RH et al (1999) Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 8:367–370

    Article  CAS  PubMed  Google Scholar 

  32. Jang IJ, Shin SG, Lee KH et al (1996) Erythrocyte thiopurine methyltransferase activity in a Korean population. Br J Clin Pharmacol 42:638–641

    CAS  PubMed  Google Scholar 

  33. Weinshilboum RM, Sladek SL (1980) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32:651–662

    CAS  PubMed  Google Scholar 

  34. Collie-Duguid ES, Pritchard SC, Powrie RH et al (1999) The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 9:37–42

    Article  CAS  PubMed  Google Scholar 

  35. Hindorf U, Lyrenas E, Nilsson A et al (2004) Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease. Scand J Gastroenterol 39:1105–1112

    Article  CAS  PubMed  Google Scholar 

  36. Schaeffeler E, Fischer C, Brockmeier D et al (2004) Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14:407–417

    Article  CAS  PubMed  Google Scholar 

  37. Yan L, Zhang S, Eiff B et al (2000) Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis. Clin Pharmacol Ther 68:210–219

    Article  CAS  PubMed  Google Scholar 

  38. King TE Jr, Safrin S, Starko KM et al (2005) Analyses of efficacy end points in a controlled trial of interferon-{gamma}1b for idiopathic pulmonary fibrosis. Chest 127:171–177

    Article  CAS  PubMed  Google Scholar 

  39. Winterbauer RH, Hammar SP, Hallman KO et al (1978) Diffuse interstitial pneumonitis clinicopathologic correlations in 20 patients treated with prednisone/azathioprine. Am J Med 65:661–672

    Article  CAS  PubMed  Google Scholar 

  40. Present DH, Meltzer SJ, Krumholz MP et al (1989) 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 111:641–649

    CAS  PubMed  Google Scholar 

  41. www.drugstore.com. Accessed 10 Sept 2008

  42. Collard HR, Loyd JE, King TE Jr et al (2007) Current diagnosis and management of idiopathic pulmonary fibrosis: a survey of academic physicians. Respir Med 101:2011–2016

    Article  PubMed  Google Scholar 

  43. Eldar-Lissai A, Cosler LE, Culakova E et al (2008) Economic analysis of prophylactic pegfilgrastim in adult cancer patients receiving chemotherapy. Value Health 11:172–179

    Article  PubMed  Google Scholar 

  44. Vogel CL, Wojtukiewicz MZ, Carroll RR et al (2005) First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23:1178–1184

    Article  CAS  PubMed  Google Scholar 

  45. Talcott JA (2000) Outpatient management of febrile neutropenia. Int J Antimicrob Agents 16:169–171

    Article  CAS  PubMed  Google Scholar 

  46. Tomioka H, Imanaka K, Hashimoto K et al (2007) Health-related quality of life in patients with idiopathic pulmonary fibrosis—cross-sectional and longitudinal study. Intern Med 46:1533–1542

    Article  PubMed  Google Scholar 

  47. Martinez F, Bradford W, Safrin S et al (2003) Rates and characteristics of death in patients with idiopathic pulmonary fibrosis (IPF). Chest 124:117S

    Google Scholar 

  48. Flaherty KR, Mumford JA, Murray S et al (2003) Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 168:543–548

    Article  PubMed  Google Scholar 

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Acknowledgments

Drs. Hagaman, Kinder, and Eckman were involved in conception, data collection and analysis, and manuscript preparation.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, 231 Albert Sabin Way ML 0564, Cincinnati, OH, 45267, USA

    Jared T. Hagaman & Brent W. Kinder

  2. Department of Internal Medicine, Division of General Internal Medicine, University of Cincinnati, Cincinnati, OH, USA

    Mark H. Eckman

Authors
  1. Jared T. Hagaman
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Corresponding author

Correspondence to Jared T. Hagaman.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00408-011-9290-7.

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Hagaman, J.T., Kinder, B.W. & Eckman, M.H. Thiopurine S-Methyltranferase Testing in Idiopathic Pulmonary Fibrosis: A Pharmacogenetic Cost-Effectiveness Analysis. Lung 188, 125–132 (2010). https://doi.org/10.1007/s00408-009-9217-8

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