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Azathioprine and 6-mercaptopurine and autoimmune hepatitis
June 1996
CORRESPONDENCE 2027
determining which variables will impact cost-effectiveness. Once there are real data, rather than assumptions, models such as that developed by the Office of Technology Assessment2 should be used to determine a more precise calculation of the cost of quality adjusted life years saved by screening. In the meantime, this model can highlight potential limitations of screening and lead to development of improved strategies in the future. Perhaps the most important variable is patient compliance, which has a significant impact on all of the screening strategies, a point reemphasized by Tierney and Fendrick. In my view, the model emphasizes the need to redouble our efforts to improve patient compliance through educational programs directed at both physicians and patients. DAVID LIEBERMAN, M.D.
Division of Gastroenterology Oregon Health Sciences University and Gastroenterology Section Portland VA Medical Center Portland, Oregon 97207 1. Lieberman DA. Cost-effectiveness model for colon cancer screening. Gastroenterology 1995;109:1781–1790. 2. Wagner JL, Herdman RC, Wadhwa S. Cost-effectiveness of colorectal cancer screening in the elderly. Ann Intern Med 1991;115: 807–817. 3. Selby JV, Friedman GD, Quesenberry CP Jr, Weiss NS. A casecontrol study of screening sigmoidscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653–657. 4. Newcomb PA, Norfleet RG, Storer BE, Surawicz TS, Marcus PM. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992;84:1572–1575. 5. Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, Ederer F. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365–1371.
Azathioprine and 6-Mercaptopurine and Autoimmune Hepatitis Dear Sir: Pratt et al. are to be commended for their insightful report regarding the use of azathioprine (AZA) and 6-mercaptopurine (6-MP) in the treatment of autoimmune hepatitis.1 One of the case records included (patient 1) describes a documented biochemical and histological response to treatment with a combination of glucocorticoids and 6-MP after the patient did not achieve remission while undergoing therapy using a combination of glucocorticoids and AZA. Glucocorticoid therapy was subsequently withdrawn, and the patient was successfully maintained on 6-MP alone. In their discussion, the authors suggest that AZA may not always be a superior immunosuppressant and, in this isolated situation, 6-MP was more effective. Our concern regarding this conclusion relates to the authors’ use of ‘‘similar’’ doses of the two immunosuppressants on a milligram per kilogram basis. Because AZA is a prodrug and the two immunosuppressants have both different bioavailabilities and molecular weights, one cannot assume that equivalent oral doses on a milligram per kilogram basis will yield comparable immunosuppressive effects.2 – 4 Specifically, when comparing oral dosing of AZA and 6-MP, a conversion factor of 0.48 [(0.48)(AZA) Å 6-MP] has been used to account for the metabolism of AZA to 6-MP and a molecular weight ratio of 0.55.5 Given the above considerations, in addition to the other possible explanations outlined by the investigators, one must also consider that patient 1 may have ultimately responded to AZA had an ‘‘equivalent
/ 5E0E$$0065
05-07-96 00:34:11
gasa
immunosuppressive dose’’ been used (i.e., 75 mg 6-MP/0.48 Å 156 mg AZA). The patient’s superior response to 6-MP may simply have reflected the higher ‘‘immunosuppressive dose’’ that was used. JOSEPH C. YARZE, M.D., F.A.C.P. KEVIN J. HERLIHY, M.D. HOWARD P. FRITZ, M.D. ANNA M. POULOS, M.D.
Gastroenterology Associates of Northern New York 3 Irongate Center P. O. Box 2368 Glens Falls, New York 12801 1. Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996;110:271–274. 2. Zimm S, Collins JN, Riccardi R, O’Neil D, Narang PK, Chabner B, Poplack DG. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 1983;308:1005–1009. 3. Van Os EC, Zins BJ, Sandborn WJ, Mays DC, Schriver ZE, Tremaine WJ, Mahoney DW, Zinsmeister AR, Lipsky JJ. Azathioprine pharmacokinetics following single dose IV, oral, delayed-release oral and rectal foam administration (abstr). Gastroenterology 1995;108: A934. 4. Odlind B, Hartvig P, Lindstrom B, Lonnerholm G, Tufveson G, Gresberg N. Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients. Int J Immunopharmacol 1986;8:1–11. 5. Sandborn WJ, Van Os EC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn’s disease. Gastroenterology 1995;109:1808–1817.
Reply. We thank Dr. Yarze and colleagues for their interest in our recent report.1 While the conversion value mentioned by them is useful for comparing the intravenous dosing of AZA and 6-MP,2 we do not believe that there are data supporting its validity for an oral route of administration. Both agents have low and variable bioavailabilities when given orally, and at least one study has shown that AZA is better absorbed from the gastrointestinal tract.3 Therefore, although there may well have been some degree of difference in the ‘‘immunosuppressive’’ dosing of the AZA and 6-MP in patient 1, we do not believe that the 75 mg (1.5 mg/kg) of 6-MP given to the patient is equal to 156 mg (3.125 mg/kg) of AZA. In addition, we were compelled to stop AZA administration because of a significant worsening of the aminotransferase levels despite a stable dose of glucocorticoids during therapy. DANIEL S. PRATT, M.D. MARSHALL M. KAPLAN, M.D.
Division of Gastroenterology New England Medical Center Tufts University School of Medicine Boston, Massachusetts 02111 1. Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996;110:271–274. 2. Sandborn WJ, VanOs EC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn’s disease. Gastroenterology 1995;109:1808–1817. 3. Elion GB. The pharmacology of azathioprine. Ann NY Acad Sci 1993;685:400–407.
WBS-Gastro
CORRESPONDENCE 2027
determining which variables will impact cost-effectiveness. Once there are real data, rather than assumptions, models such as that developed by the Office of Technology Assessment2 should be used to determine a more precise calculation of the cost of quality adjusted life years saved by screening. In the meantime, this model can highlight potential limitations of screening and lead to development of improved strategies in the future. Perhaps the most important variable is patient compliance, which has a significant impact on all of the screening strategies, a point reemphasized by Tierney and Fendrick. In my view, the model emphasizes the need to redouble our efforts to improve patient compliance through educational programs directed at both physicians and patients. DAVID LIEBERMAN, M.D.
Division of Gastroenterology Oregon Health Sciences University and Gastroenterology Section Portland VA Medical Center Portland, Oregon 97207 1. Lieberman DA. Cost-effectiveness model for colon cancer screening. Gastroenterology 1995;109:1781–1790. 2. Wagner JL, Herdman RC, Wadhwa S. Cost-effectiveness of colorectal cancer screening in the elderly. Ann Intern Med 1991;115: 807–817. 3. Selby JV, Friedman GD, Quesenberry CP Jr, Weiss NS. A casecontrol study of screening sigmoidscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653–657. 4. Newcomb PA, Norfleet RG, Storer BE, Surawicz TS, Marcus PM. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992;84:1572–1575. 5. Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, Ederer F. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365–1371.
Azathioprine and 6-Mercaptopurine and Autoimmune Hepatitis Dear Sir: Pratt et al. are to be commended for their insightful report regarding the use of azathioprine (AZA) and 6-mercaptopurine (6-MP) in the treatment of autoimmune hepatitis.1 One of the case records included (patient 1) describes a documented biochemical and histological response to treatment with a combination of glucocorticoids and 6-MP after the patient did not achieve remission while undergoing therapy using a combination of glucocorticoids and AZA. Glucocorticoid therapy was subsequently withdrawn, and the patient was successfully maintained on 6-MP alone. In their discussion, the authors suggest that AZA may not always be a superior immunosuppressant and, in this isolated situation, 6-MP was more effective. Our concern regarding this conclusion relates to the authors’ use of ‘‘similar’’ doses of the two immunosuppressants on a milligram per kilogram basis. Because AZA is a prodrug and the two immunosuppressants have both different bioavailabilities and molecular weights, one cannot assume that equivalent oral doses on a milligram per kilogram basis will yield comparable immunosuppressive effects.2 – 4 Specifically, when comparing oral dosing of AZA and 6-MP, a conversion factor of 0.48 [(0.48)(AZA) Å 6-MP] has been used to account for the metabolism of AZA to 6-MP and a molecular weight ratio of 0.55.5 Given the above considerations, in addition to the other possible explanations outlined by the investigators, one must also consider that patient 1 may have ultimately responded to AZA had an ‘‘equivalent
/ 5E0E$$0065
05-07-96 00:34:11
gasa
immunosuppressive dose’’ been used (i.e., 75 mg 6-MP/0.48 Å 156 mg AZA). The patient’s superior response to 6-MP may simply have reflected the higher ‘‘immunosuppressive dose’’ that was used. JOSEPH C. YARZE, M.D., F.A.C.P. KEVIN J. HERLIHY, M.D. HOWARD P. FRITZ, M.D. ANNA M. POULOS, M.D.
Gastroenterology Associates of Northern New York 3 Irongate Center P. O. Box 2368 Glens Falls, New York 12801 1. Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996;110:271–274. 2. Zimm S, Collins JN, Riccardi R, O’Neil D, Narang PK, Chabner B, Poplack DG. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 1983;308:1005–1009. 3. Van Os EC, Zins BJ, Sandborn WJ, Mays DC, Schriver ZE, Tremaine WJ, Mahoney DW, Zinsmeister AR, Lipsky JJ. Azathioprine pharmacokinetics following single dose IV, oral, delayed-release oral and rectal foam administration (abstr). Gastroenterology 1995;108: A934. 4. Odlind B, Hartvig P, Lindstrom B, Lonnerholm G, Tufveson G, Gresberg N. Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients. Int J Immunopharmacol 1986;8:1–11. 5. Sandborn WJ, Van Os EC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn’s disease. Gastroenterology 1995;109:1808–1817.
Reply. We thank Dr. Yarze and colleagues for their interest in our recent report.1 While the conversion value mentioned by them is useful for comparing the intravenous dosing of AZA and 6-MP,2 we do not believe that there are data supporting its validity for an oral route of administration. Both agents have low and variable bioavailabilities when given orally, and at least one study has shown that AZA is better absorbed from the gastrointestinal tract.3 Therefore, although there may well have been some degree of difference in the ‘‘immunosuppressive’’ dosing of the AZA and 6-MP in patient 1, we do not believe that the 75 mg (1.5 mg/kg) of 6-MP given to the patient is equal to 156 mg (3.125 mg/kg) of AZA. In addition, we were compelled to stop AZA administration because of a significant worsening of the aminotransferase levels despite a stable dose of glucocorticoids during therapy. DANIEL S. PRATT, M.D. MARSHALL M. KAPLAN, M.D.
Division of Gastroenterology New England Medical Center Tufts University School of Medicine Boston, Massachusetts 02111 1. Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996;110:271–274. 2. Sandborn WJ, VanOs EC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn’s disease. Gastroenterology 1995;109:1808–1817. 3. Elion GB. The pharmacology of azathioprine. Ann NY Acad Sci 1993;685:400–407.
WBS-Gastro