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Rational selection of oral 5-aminosalicylate formulations and prodrugs for the treatment of ulcerative colitis1
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 97, No. 12, 2002 ISSN 0002-9270/02/$22.00
EDITORIALS Rational Selection of Oral 5-Aminosalicylate Formulations and Prodrugs for the Treatment of Ulcerative Colitis Multiple delayed-release and sustained-release formulations and prodrugs have been designed to prevent orally administered 5-aminosalicylate (5-ASA) from being absorbed in the proximal small intestine and to release the majority of the 5-ASA dose directly in the distal ileum and/or colon for topical treatment of ulcerative colitis. Sulfasalazine (1), olsalazine (2), and balsalazide (3) are prodrugs that contain azo bonds, which are cleaved by bacterial azo-reductase enzymes in the colonic lumen to release free 5-ASA (4). Sulfasalazine also releases sulfapyridine, and balsalazide also releases 4-aminobenzoyl--alanine. Asacol is a delayedrelease formulation that releases in the terminal ileum and cecum at pH 7 (5); Salofalk, Mesasal, and Claversal are delayed-release formulations that release beginning in the midileum at pH 6; Pentasa is a sustained-release formulation that releases throughout the small and large intestine beginning in the duodenum and ending in the rectum (6). A significant portion of the free 5-ASA released topically by the various oral 5-ASA formulations and prodrugs is absorbed into the colonic epithelium, where it undergoes extensive metabolism to N-acetyl-5-ASA (N-Ac-5-ASA) by the enzyme N-acetyltransferase 1 (7, 8). From the colonic epithelium, N-Ac-5-ASA is either absorbed systemically into the blood and then excreted in the urine, or secreted back into the lumen by the membranebound drug efflux pump P-glycoprotein and excreted in the feces (9 –11). Some free 5-ASA is also absorbed systemically from the colonic epithelium (followed by additional metabolism to N-Ac-5-ASA by N-acetyltransferase 1 in the liver), and then excreted in the urine as either free 5-ASA or N-Ac-5-ASA (9, 10). The pharmacokinetic profiles, safety, and efficacy of these oral 5-ASA formulations are reviewed below, to provide physicians with relevant practical information when they advise patients with ulcerative colitis regarding selection of one of these medications. The first question that clinicians must ask is whether there are clinically important differences in the pharmacokinetic profiles of the oral 5-ASA drugs. Some pharmacological studies have reported that plasma concentrations and/or urinary excretion of 5-ASA and N-Ac-5-ASA are significantly greater in subjects treated with Asacol, Pentasa, or Salofalk compared with sulfasalazine and olsalazine (12– Financial Disclosure: William J. Sandborn, M.D., has received research support from and/or served as a consultant for Procter & Gamble Pharmaceuticals and Salix Pharmaceuticals, and has participated in continuing medical education events sponsored indirectly by Procter & Gamble Pharmaceuticals, Salix Pharmaceuticals, Shire Pharmaceuticals, Ferring, and Falk Pharma.
15). The design of these studies is flawed in many instances because: 1) the same total daily dose of 5-ASA was not administered (13–15); 2) the measurement of plasma 5-ASA and N-Ac-5-ASA was determined at a only one or two points in time rather than at multiple time points (12–15); 3) one-sided statistical tests were used for statistical analysis (12, 15); and 4) comparisons of ratios of drug or metabolite concentrations rather than direct comparisons of the concentrations themselves were used for statistical analysis (15). In contrast, a pharmacokinetic study using data obtained at multiple sampling points showed nearly identical Cmax and area under the curve values for equimolar doses of Asacol and balsalazide (16). A systematic review showed comparable ranges of systemic absorption of 5-ASA as measured by 24-h urinary excretion of total 5-ASA (free 5-ASA plus N-Ac-5-ASA) after treatment with Pentasa (23– 36%), Asacol (11– 40%), balsalazide (12–35%), sulfasalazine (8 –37%), and olsalazine (5–31%) (17). These studies suggest that systemic exposure to 5-ASA, as measured by plasma pharmacokinetics and urinary excretion of total 5-ASA, is similar for all oral 5-ASA formulations and 5-ASA prodrugs. Thus, it is not rational to select an oral 5-ASA agent on the basis of the pharmacokinetic profile. The second question clinicians must ask is whether there are clinically important differences in the safety profiles of the oral 5-ASA drugs. The safety of both the parent compounds and 5-ASA itself must be considered. The systemic absorption of sulfapyridine from the colon after cleavage of the azo bond of sulfasalazine leads to multiple side effects, including headache, epigastric pain, nausea and vomiting, skin rash, fever, aplastic anemia, leukopenia, agranulocytosis, folate deficiency, pancreatitis, systemic lupus erythematosus, sulfonamide-induced toxic epidermal necrolysis, Stevens-Johnson syndrome, pulmonary dysfunction, and male infertility (18, 19). The 5-ASA dimer olsalazine leads to worsened diarrhea resulting from ileal secretion in some patients (20), particularly in the setting of active ulcerative colitis (21). Investigators have suggested that greater systemic absorption of 5-ASA from delayed-release or sustained-release oral 5-ASA formulations may lead to nephrotoxicity (12–15), and there are case series of interstitial nephritis in patients treated with 5-ASA (22, 23). However, other studies have shown that renal tubular proteinuria correlates with the disease activity of the inflammatory bowel disease (24 –26), that the glomerular filtration rate does not change during maintenance therapy with 5-ASA or olsalazine (27), and that the frequency of renal insufficiency was low in large safety and pharmacovigilance data bases for Asacol and Pentasa (28, 29). These reports suggest that 5-ASA at the doses used in clinical practice does not result in clinically important effects on renal function. Thus, the important safety considerations for 5-ASA therapy in pa-
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tients with ulcerative colitis are adverse events caused by sulfapyridine in patients treated with sulfasalazine, and olsalazine-related diarrhea, not 5-ASA nephrotoxicity. The third question clinicians must ask is whether there are clinically important differences in the efficacy of the oral 5-ASA drugs. Two meta-analyses including 22 studies of oral 5-ASA (includes Asacol, Pentasa, Mesasal, Claversal, olsalazine, balsalazide) compared with sulfasalazine in patients with ulcerative colitis showed no significant difference between the two treatments for the endpoints of induction of remission and maintenance of remission at 1 yr (30, 31). To further support the conclusion that there is no difference in efficacy between these 5-ASA agents, it should be pointed out that only two trials have ever demonstrated statistical differences in efficacy (32, 33), and in each case, other similar trials did not support the findings of superiority (34 –39). A case in point is three trials comparing the efficacy of balsalazide and Asacol for active ulcerative colitis (33, 38, 39). A 101-patient study by Green et al. demonstrated superiority of balsalazide 6.75 g over Asacol 2.4 g for induction of complete remission at wk 12 (62% vs 45%, p ⬍ 0.05) (33). In a second study by Levine et al. of 98 patients treated with balsalazide 6.75 g or Asacol 2.4 g, there was no difference in the primary endpoint of the study defined as a significant difference in rectal bleeding and at least one other sign or symptom at wk 8 (65% vs 53%, p ⫽ 0.275) (38). In a third study by Pruitt et al. (39) of 173 patients treated with balsalazide 6.75 g or Asacol 2.4 g, there was no difference in the primary endpoint of the study defined as a significant difference in the proportion of patients in symptomatic remission at wk 8 (52% vs 49%, p ⫽ ns) (39). Secondary endpoints in the studies by Levine et al. (38) and Pruitt et al. (39), such as faster time to onset of improvement, and improvement or remission in patients with new onset or left-sided disease, which suggested superiority of balsalazide over Asacol, can only be considered exploratory given that the primary endpoints for the studies demonstrated no significant difference between the two 5-ASA therapies. Another study comparing balsalazide 3 g (1 g of 5-ASA), Salofalk 1.5 g (1.5 g of 5-ASA), and balsalazide 6 g (2 g of 5-ASA) for maintenance of remission demonstrated remission rates at 26 wk of 44%, 57%, and 78% (p value for Salofalk 1.5 g vs balsalazide 6 g ⫽ 0.045; this was not adjusted for multiple comparisons) (40). This study showed evidence of a dose-response effect for 5-ASA, with the difference between Salofalk 1.5 g (1.5 g of 5-ASA) and balsalazide 6 g (2 g of 5-ASA) equivocal for statistical significance, depending on whether or not there was adjustment for multiple comparisons. Studies comparing balsalazide and sulfasalazine have not shown significant differences in efficacy (41– 43). For clinicians to accept that one 5-ASA therapy is superior to another, at least two adequate and wellcontrolled trials demonstrating statistically significant superiority for the prespecified primary endpoint are required (replication of results for the primary endpoint is needed). No 5-ASA agent meets this requirement. Thus, all of the 5-ASA
AJG – Vol. 97, No. 12, 2002
agents can be considered effective for the treatment of ulcerative colitis, and from a practical standpoint, they can be considered therapeutically equivalent at equimolar doses. How then should practicing clinicians use the available evidence to select an oral 5-ASA formulation or 5-ASA prodrug to treat patients with ulcerative colitis? As outlined above, pharmacokinetic studies and efficacy studies suggest that both systemic exposure to 5-ASA and efficacy are similar for all oral 5-ASA formulations and 5-ASA prodrugs. The glomerular filtration rate does not change during maintenance therapy with oral 5-ASA or olsalazine, and clinically important nephrotoxicity is exceedingly rare for both Asacol and Pentasa, suggesting that the systemic exposure to 5-ASA that occurs at 5-ASA doses used in clinical practice is safe for all drugs in this class. First-line treatment with sulfasalazine and olsalazine may not be preferable because of the high frequency of adverse events. When selecting among the remaining agents, other factors such as availability of dose-response data for 5-ASA doses up to 4 – 4.8 g/day of 5-ASA (44, 45), compliance issues related to dose forms (size of dose form and total number of tablets or capsules per day), and price should be considered. William J. Sandborn, M.D. Inflammatory Bowel Disease Clinic Division of Gastroenterology and Hepatology Mayo Clinic and Mayo Foundation Rochester, Minnesota
REFERENCES 1. Das KM, Dubin R. Clinical pharmacokinetics of sulphasalazine. Clin Pharmacokinet 1976;1:406 –25. 2. Wadworth AN, Fitton A. Olsalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease. Drugs 1991;41:647– 64. 3. Ragunath K, Williams JG. Review article: Balsalazide therapy in ulcerative colitis. Aliment Pharmacol Ther 2001;15:1549 – 54. 4. Peppercorn MA, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 1972;181:555– 62. 5. Prakash A, Markham A. Oral delayed-release mesalazine: A review of its use in ulcerative colitis and Crohn’s disease. Drugs 1999;57:383– 408. 6. Clemett D, Markham A. Prolonged-release mesalazine: A review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000;59:929 –56. 7. Allgayer H, Ahnfelt NO, Kruis W, et al. Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease. Gastroenterology 1989;97:38 – 41. 8. Ireland A, Priddle JD, Jewell DP. Acetylation of 5-aminosalicylic acid by isolated human colonic epithelial cells. Clin Sci (Lond) 1990;78:105–11. 9. Goebell H, Klotz U, Nehlsen B, Layer P. Oroileal transit of slow release 5-aminosalicylic acid. Gut 1993;34:669 –75. 10. Layer PH, Goebell H, Keller J, et al. Delivery and fate of oral mesalamine microgranules within the human small intestine. Gastroenterology 1995;108:1427–33. 11. Zhou SY, Fleisher D, Pao LH, et al. Intestinal metabolism and
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12.
13.
14.
15.
16. 17.
18.
19. 20.
21. 22. 23. 24. 25. 26.
27.
28. 29.
30.
transport of 5-aminosalicylate. Drug Metab Dispos 1999;27: 479 – 85. Staerk Laursen L, Stokholm M, Bukhave K, et al. Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: Comparison of intraluminal colonic concentrations, serum values, and urinary excretion. Gut 1990;31:1271– 6. Christensen LA, Fallingborg J, Jacobsen BA, et al. Comparative bioavailability of 5-aminosalicylic acid from a controlled release preparation and an azo-bond preparation. Aliment Pharmacol Ther 1994;8:289 –94. Stretch GL, Campbell BJ, Dwarakanath AD, et al. 5-amino salicylic acid absorption and metabolism in ulcerative colitis patients receiving maintenance sulphasalazine, olsalazine or mesalazine. Aliment Pharmacol Ther 1996;10:941–7. Karamanolis DG, Papatheodoridis GV, Xourgias V. Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. Eur J Gastroenterol Hepatol 1996;8:1083– 8. Sandborn WJ, Hanauer SB, Buch A. Comparable systemic absorption of 5-ASA and N-AC-5-ASA from U.S. Asacol and Colazal. Am J Gastroenterol 2002;97:S263. Sandborn WJ, Hanauer SB. The pharmacokinetic profiles of oral 5ASA formulations used in the management of ulcerative colitis: A systematic review. Am J Gastroenterol 2002;97: S269. Das KM, Eastwood MA, McManus JP, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 1973;289:491–5. Taffet SL, Das KM. Sulfasalazine. Adverse effects and desensitization. Dig Dis Sci 1983;28:833– 42. Pamukcu R, Hanauer SB, Chang EB. Effect of disodium azodisalicylate on electrolyte transport in rabbit ileum and colon in vitro. Comparison with sulfasalazine and 5-aminosalicylic acid. Gastroenterology 1988;95:975– 81. Feurle GE, Theuer D, Velasco S, et al. Olsalazine versus placebo in the treatment of mild to moderate ulcerative colitis: A randomised double blind trial. Gut 1989;30:1354 – 61. Brouillard M, Gheerbrant JD, Gheysens Y, et al. Chronic interstitial nephritis and mesalazine: 3 new cases? Gastroenterol Clin Biol 1998;22:724 – 6. Calvino J, Romero R, Pintos E, et al. Mesalazine-associated tubulo-interstitial nephritis in inflammatory bowel disease. Clin Nephrol 1998;49:265–7. Riley SA, Lloyd DR, Mani V. Tests of renal function in patients with quiescent colitis: Effects of drug treatment. Gut 1992;33:1348 –52. Schreiber S, Hamling J, Zehnter E, et al. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut 1997;40:761– 6. Fraser JS, Muller AF, Smith DJ, et al. Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy. Aliment Pharmacol Ther 2001;15: 1131–7. Mahmud N, O’Toole D, O’Hare N, et al. Evaluation of renal function following treatment with 5-aminosalicylic acid derivatives in patients with ulcerative colitis. Aliment Pharmacol Ther 2002;16:207–15. Hanauer SB, Verst-Brasch C, Regalli G. Renal safety of longterm mesalamine therapy in inflammatory bowel disease (IBD). Gastroenterology 1997;112:A991 (abstract). Marteau P, Nelet F, Le Lu M, Devaux C. Adverse events in patients treated with 5-aminosalicyclic acid: 1993–1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther 1996:10:949 –56. Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited:
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31. 32. 33.
34.
35.
36. 37.
38.
39.
40.
41.
42.
43.
44. 45.
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A meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis. Ann Intern Med 1993;118:540 –9. Sutherland LR, Roth DE, Beck PL. Alternatives to sulfasalazine: A meta-analysis of 5-ASA in the treatment of ulcerative colitis. Inflamm Bowel Dis 1997;3:65–78. Courtney MG, Nunes DP, Bergin CF, et al. Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis. Lancet 1992;339:1279 – 81. Green JR, Lobo AJ, Holdsworth CD, et al. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group. Gastroenterology 1998;114:15–22. Kiilerich S, Ladefoged K, Rannem T, Ranlov PJ. Prophylactic effects of olsalazine v sulphasalazine during 12 months maintenance treatment of ulcerative colitis. The Danish Olsalazine Study Group. Gut 1992;33:252–5. Kruis W, Judmaier G, Kayasseh L, et al. Double-blind dosefinding study of olsalazine versus sulphasalazine as maintenance therapy for ulcerative colitis. Eur J Gastroenterol Hepatol 1995;7:391– 6. Nilsson A, Danielsson A, Lofberg R, et al. Olsalazine versus sulphasalazine for relapse prevention in ulcerative colitis: A multicenter study. Am J Gastroenterol 1995;90:381–7. Rijk MC, van Lier HJ, van Tongeren JH. Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: A prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study Group. Am J Gastroenterol 1992;87:438 – 42. Levine DS, Riff DS, Pruitt R, et al. A randomized, doubleblind, dose-response comparison of balsalazide 6.75 g, balsalazide 2.25 g, and mesalamine 2.4 g in the treatment of active, mild to moderate ulcerative colitis. Am J Gastroenerol 2002;97:1398 –1407. Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild to moderate ulcerative colitis. Am J Gastroenterol 2002;97:3078 – 86. Kruis W, Schreiber S, Theuer D, et al. Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses. Gut 2001;49:783–9. Green JR, Mansfield JC, Gibson JA, et al. A double-blind comparison of balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or relapsed active ulcerative colitis. Aliment Pharmacol Ther 2002;16:61– 8. Mansfield JC, Giaffer MH, Cann PA, et al. A double-blind comparison of balsalazide, 6.75 g, and sulfasalazine, 3 g, as sole therapy in the management of ulcerative colitis. Aliment Pharmacol Ther 2002;16:69 –77. Green JR, Gibson JA, Kerr GD, et al. Maintenance of remission of ulcerative colitis: A comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator Group. Aliment Pharmacol Ther 1998;12:1207–16. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625–9. Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: Results of a controlled trial. Pentasa Study Group. Am J Gastroenterol 1993;88:1188 –97.
Reprint requests and correspondence: William J. Sandborn, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Received June 26, 2002; accepted Aug. 27, 2002.
Vol. 97, No. 12, 2002 ISSN 0002-9270/02/$22.00
EDITORIALS Rational Selection of Oral 5-Aminosalicylate Formulations and Prodrugs for the Treatment of Ulcerative Colitis Multiple delayed-release and sustained-release formulations and prodrugs have been designed to prevent orally administered 5-aminosalicylate (5-ASA) from being absorbed in the proximal small intestine and to release the majority of the 5-ASA dose directly in the distal ileum and/or colon for topical treatment of ulcerative colitis. Sulfasalazine (1), olsalazine (2), and balsalazide (3) are prodrugs that contain azo bonds, which are cleaved by bacterial azo-reductase enzymes in the colonic lumen to release free 5-ASA (4). Sulfasalazine also releases sulfapyridine, and balsalazide also releases 4-aminobenzoyl--alanine. Asacol is a delayedrelease formulation that releases in the terminal ileum and cecum at pH 7 (5); Salofalk, Mesasal, and Claversal are delayed-release formulations that release beginning in the midileum at pH 6; Pentasa is a sustained-release formulation that releases throughout the small and large intestine beginning in the duodenum and ending in the rectum (6). A significant portion of the free 5-ASA released topically by the various oral 5-ASA formulations and prodrugs is absorbed into the colonic epithelium, where it undergoes extensive metabolism to N-acetyl-5-ASA (N-Ac-5-ASA) by the enzyme N-acetyltransferase 1 (7, 8). From the colonic epithelium, N-Ac-5-ASA is either absorbed systemically into the blood and then excreted in the urine, or secreted back into the lumen by the membranebound drug efflux pump P-glycoprotein and excreted in the feces (9 –11). Some free 5-ASA is also absorbed systemically from the colonic epithelium (followed by additional metabolism to N-Ac-5-ASA by N-acetyltransferase 1 in the liver), and then excreted in the urine as either free 5-ASA or N-Ac-5-ASA (9, 10). The pharmacokinetic profiles, safety, and efficacy of these oral 5-ASA formulations are reviewed below, to provide physicians with relevant practical information when they advise patients with ulcerative colitis regarding selection of one of these medications. The first question that clinicians must ask is whether there are clinically important differences in the pharmacokinetic profiles of the oral 5-ASA drugs. Some pharmacological studies have reported that plasma concentrations and/or urinary excretion of 5-ASA and N-Ac-5-ASA are significantly greater in subjects treated with Asacol, Pentasa, or Salofalk compared with sulfasalazine and olsalazine (12– Financial Disclosure: William J. Sandborn, M.D., has received research support from and/or served as a consultant for Procter & Gamble Pharmaceuticals and Salix Pharmaceuticals, and has participated in continuing medical education events sponsored indirectly by Procter & Gamble Pharmaceuticals, Salix Pharmaceuticals, Shire Pharmaceuticals, Ferring, and Falk Pharma.
15). The design of these studies is flawed in many instances because: 1) the same total daily dose of 5-ASA was not administered (13–15); 2) the measurement of plasma 5-ASA and N-Ac-5-ASA was determined at a only one or two points in time rather than at multiple time points (12–15); 3) one-sided statistical tests were used for statistical analysis (12, 15); and 4) comparisons of ratios of drug or metabolite concentrations rather than direct comparisons of the concentrations themselves were used for statistical analysis (15). In contrast, a pharmacokinetic study using data obtained at multiple sampling points showed nearly identical Cmax and area under the curve values for equimolar doses of Asacol and balsalazide (16). A systematic review showed comparable ranges of systemic absorption of 5-ASA as measured by 24-h urinary excretion of total 5-ASA (free 5-ASA plus N-Ac-5-ASA) after treatment with Pentasa (23– 36%), Asacol (11– 40%), balsalazide (12–35%), sulfasalazine (8 –37%), and olsalazine (5–31%) (17). These studies suggest that systemic exposure to 5-ASA, as measured by plasma pharmacokinetics and urinary excretion of total 5-ASA, is similar for all oral 5-ASA formulations and 5-ASA prodrugs. Thus, it is not rational to select an oral 5-ASA agent on the basis of the pharmacokinetic profile. The second question clinicians must ask is whether there are clinically important differences in the safety profiles of the oral 5-ASA drugs. The safety of both the parent compounds and 5-ASA itself must be considered. The systemic absorption of sulfapyridine from the colon after cleavage of the azo bond of sulfasalazine leads to multiple side effects, including headache, epigastric pain, nausea and vomiting, skin rash, fever, aplastic anemia, leukopenia, agranulocytosis, folate deficiency, pancreatitis, systemic lupus erythematosus, sulfonamide-induced toxic epidermal necrolysis, Stevens-Johnson syndrome, pulmonary dysfunction, and male infertility (18, 19). The 5-ASA dimer olsalazine leads to worsened diarrhea resulting from ileal secretion in some patients (20), particularly in the setting of active ulcerative colitis (21). Investigators have suggested that greater systemic absorption of 5-ASA from delayed-release or sustained-release oral 5-ASA formulations may lead to nephrotoxicity (12–15), and there are case series of interstitial nephritis in patients treated with 5-ASA (22, 23). However, other studies have shown that renal tubular proteinuria correlates with the disease activity of the inflammatory bowel disease (24 –26), that the glomerular filtration rate does not change during maintenance therapy with 5-ASA or olsalazine (27), and that the frequency of renal insufficiency was low in large safety and pharmacovigilance data bases for Asacol and Pentasa (28, 29). These reports suggest that 5-ASA at the doses used in clinical practice does not result in clinically important effects on renal function. Thus, the important safety considerations for 5-ASA therapy in pa-
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tients with ulcerative colitis are adverse events caused by sulfapyridine in patients treated with sulfasalazine, and olsalazine-related diarrhea, not 5-ASA nephrotoxicity. The third question clinicians must ask is whether there are clinically important differences in the efficacy of the oral 5-ASA drugs. Two meta-analyses including 22 studies of oral 5-ASA (includes Asacol, Pentasa, Mesasal, Claversal, olsalazine, balsalazide) compared with sulfasalazine in patients with ulcerative colitis showed no significant difference between the two treatments for the endpoints of induction of remission and maintenance of remission at 1 yr (30, 31). To further support the conclusion that there is no difference in efficacy between these 5-ASA agents, it should be pointed out that only two trials have ever demonstrated statistical differences in efficacy (32, 33), and in each case, other similar trials did not support the findings of superiority (34 –39). A case in point is three trials comparing the efficacy of balsalazide and Asacol for active ulcerative colitis (33, 38, 39). A 101-patient study by Green et al. demonstrated superiority of balsalazide 6.75 g over Asacol 2.4 g for induction of complete remission at wk 12 (62% vs 45%, p ⬍ 0.05) (33). In a second study by Levine et al. of 98 patients treated with balsalazide 6.75 g or Asacol 2.4 g, there was no difference in the primary endpoint of the study defined as a significant difference in rectal bleeding and at least one other sign or symptom at wk 8 (65% vs 53%, p ⫽ 0.275) (38). In a third study by Pruitt et al. (39) of 173 patients treated with balsalazide 6.75 g or Asacol 2.4 g, there was no difference in the primary endpoint of the study defined as a significant difference in the proportion of patients in symptomatic remission at wk 8 (52% vs 49%, p ⫽ ns) (39). Secondary endpoints in the studies by Levine et al. (38) and Pruitt et al. (39), such as faster time to onset of improvement, and improvement or remission in patients with new onset or left-sided disease, which suggested superiority of balsalazide over Asacol, can only be considered exploratory given that the primary endpoints for the studies demonstrated no significant difference between the two 5-ASA therapies. Another study comparing balsalazide 3 g (1 g of 5-ASA), Salofalk 1.5 g (1.5 g of 5-ASA), and balsalazide 6 g (2 g of 5-ASA) for maintenance of remission demonstrated remission rates at 26 wk of 44%, 57%, and 78% (p value for Salofalk 1.5 g vs balsalazide 6 g ⫽ 0.045; this was not adjusted for multiple comparisons) (40). This study showed evidence of a dose-response effect for 5-ASA, with the difference between Salofalk 1.5 g (1.5 g of 5-ASA) and balsalazide 6 g (2 g of 5-ASA) equivocal for statistical significance, depending on whether or not there was adjustment for multiple comparisons. Studies comparing balsalazide and sulfasalazine have not shown significant differences in efficacy (41– 43). For clinicians to accept that one 5-ASA therapy is superior to another, at least two adequate and wellcontrolled trials demonstrating statistically significant superiority for the prespecified primary endpoint are required (replication of results for the primary endpoint is needed). No 5-ASA agent meets this requirement. Thus, all of the 5-ASA
AJG – Vol. 97, No. 12, 2002
agents can be considered effective for the treatment of ulcerative colitis, and from a practical standpoint, they can be considered therapeutically equivalent at equimolar doses. How then should practicing clinicians use the available evidence to select an oral 5-ASA formulation or 5-ASA prodrug to treat patients with ulcerative colitis? As outlined above, pharmacokinetic studies and efficacy studies suggest that both systemic exposure to 5-ASA and efficacy are similar for all oral 5-ASA formulations and 5-ASA prodrugs. The glomerular filtration rate does not change during maintenance therapy with oral 5-ASA or olsalazine, and clinically important nephrotoxicity is exceedingly rare for both Asacol and Pentasa, suggesting that the systemic exposure to 5-ASA that occurs at 5-ASA doses used in clinical practice is safe for all drugs in this class. First-line treatment with sulfasalazine and olsalazine may not be preferable because of the high frequency of adverse events. When selecting among the remaining agents, other factors such as availability of dose-response data for 5-ASA doses up to 4 – 4.8 g/day of 5-ASA (44, 45), compliance issues related to dose forms (size of dose form and total number of tablets or capsules per day), and price should be considered. William J. Sandborn, M.D. Inflammatory Bowel Disease Clinic Division of Gastroenterology and Hepatology Mayo Clinic and Mayo Foundation Rochester, Minnesota
REFERENCES 1. Das KM, Dubin R. Clinical pharmacokinetics of sulphasalazine. Clin Pharmacokinet 1976;1:406 –25. 2. Wadworth AN, Fitton A. Olsalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease. Drugs 1991;41:647– 64. 3. Ragunath K, Williams JG. Review article: Balsalazide therapy in ulcerative colitis. Aliment Pharmacol Ther 2001;15:1549 – 54. 4. Peppercorn MA, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 1972;181:555– 62. 5. Prakash A, Markham A. Oral delayed-release mesalazine: A review of its use in ulcerative colitis and Crohn’s disease. Drugs 1999;57:383– 408. 6. Clemett D, Markham A. Prolonged-release mesalazine: A review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000;59:929 –56. 7. Allgayer H, Ahnfelt NO, Kruis W, et al. Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease. Gastroenterology 1989;97:38 – 41. 8. Ireland A, Priddle JD, Jewell DP. Acetylation of 5-aminosalicylic acid by isolated human colonic epithelial cells. Clin Sci (Lond) 1990;78:105–11. 9. Goebell H, Klotz U, Nehlsen B, Layer P. Oroileal transit of slow release 5-aminosalicylic acid. Gut 1993;34:669 –75. 10. Layer PH, Goebell H, Keller J, et al. Delivery and fate of oral mesalamine microgranules within the human small intestine. Gastroenterology 1995;108:1427–33. 11. Zhou SY, Fleisher D, Pao LH, et al. Intestinal metabolism and
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12.
13.
14.
15.
16. 17.
18.
19. 20.
21. 22. 23. 24. 25. 26.
27.
28. 29.
30.
transport of 5-aminosalicylate. Drug Metab Dispos 1999;27: 479 – 85. Staerk Laursen L, Stokholm M, Bukhave K, et al. Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: Comparison of intraluminal colonic concentrations, serum values, and urinary excretion. Gut 1990;31:1271– 6. Christensen LA, Fallingborg J, Jacobsen BA, et al. Comparative bioavailability of 5-aminosalicylic acid from a controlled release preparation and an azo-bond preparation. Aliment Pharmacol Ther 1994;8:289 –94. Stretch GL, Campbell BJ, Dwarakanath AD, et al. 5-amino salicylic acid absorption and metabolism in ulcerative colitis patients receiving maintenance sulphasalazine, olsalazine or mesalazine. Aliment Pharmacol Ther 1996;10:941–7. Karamanolis DG, Papatheodoridis GV, Xourgias V. Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. Eur J Gastroenterol Hepatol 1996;8:1083– 8. Sandborn WJ, Hanauer SB, Buch A. Comparable systemic absorption of 5-ASA and N-AC-5-ASA from U.S. Asacol and Colazal. Am J Gastroenterol 2002;97:S263. Sandborn WJ, Hanauer SB. The pharmacokinetic profiles of oral 5ASA formulations used in the management of ulcerative colitis: A systematic review. Am J Gastroenterol 2002;97: S269. Das KM, Eastwood MA, McManus JP, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 1973;289:491–5. Taffet SL, Das KM. Sulfasalazine. Adverse effects and desensitization. Dig Dis Sci 1983;28:833– 42. Pamukcu R, Hanauer SB, Chang EB. Effect of disodium azodisalicylate on electrolyte transport in rabbit ileum and colon in vitro. Comparison with sulfasalazine and 5-aminosalicylic acid. Gastroenterology 1988;95:975– 81. Feurle GE, Theuer D, Velasco S, et al. Olsalazine versus placebo in the treatment of mild to moderate ulcerative colitis: A randomised double blind trial. Gut 1989;30:1354 – 61. Brouillard M, Gheerbrant JD, Gheysens Y, et al. Chronic interstitial nephritis and mesalazine: 3 new cases? Gastroenterol Clin Biol 1998;22:724 – 6. Calvino J, Romero R, Pintos E, et al. Mesalazine-associated tubulo-interstitial nephritis in inflammatory bowel disease. Clin Nephrol 1998;49:265–7. Riley SA, Lloyd DR, Mani V. Tests of renal function in patients with quiescent colitis: Effects of drug treatment. Gut 1992;33:1348 –52. Schreiber S, Hamling J, Zehnter E, et al. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut 1997;40:761– 6. Fraser JS, Muller AF, Smith DJ, et al. Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy. Aliment Pharmacol Ther 2001;15: 1131–7. Mahmud N, O’Toole D, O’Hare N, et al. Evaluation of renal function following treatment with 5-aminosalicylic acid derivatives in patients with ulcerative colitis. Aliment Pharmacol Ther 2002;16:207–15. Hanauer SB, Verst-Brasch C, Regalli G. Renal safety of longterm mesalamine therapy in inflammatory bowel disease (IBD). Gastroenterology 1997;112:A991 (abstract). Marteau P, Nelet F, Le Lu M, Devaux C. Adverse events in patients treated with 5-aminosalicyclic acid: 1993–1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther 1996:10:949 –56. Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited:
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31. 32. 33.
34.
35.
36. 37.
38.
39.
40.
41.
42.
43.
44. 45.
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A meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis. Ann Intern Med 1993;118:540 –9. Sutherland LR, Roth DE, Beck PL. Alternatives to sulfasalazine: A meta-analysis of 5-ASA in the treatment of ulcerative colitis. Inflamm Bowel Dis 1997;3:65–78. Courtney MG, Nunes DP, Bergin CF, et al. Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis. Lancet 1992;339:1279 – 81. Green JR, Lobo AJ, Holdsworth CD, et al. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group. Gastroenterology 1998;114:15–22. Kiilerich S, Ladefoged K, Rannem T, Ranlov PJ. Prophylactic effects of olsalazine v sulphasalazine during 12 months maintenance treatment of ulcerative colitis. The Danish Olsalazine Study Group. Gut 1992;33:252–5. Kruis W, Judmaier G, Kayasseh L, et al. Double-blind dosefinding study of olsalazine versus sulphasalazine as maintenance therapy for ulcerative colitis. Eur J Gastroenterol Hepatol 1995;7:391– 6. Nilsson A, Danielsson A, Lofberg R, et al. Olsalazine versus sulphasalazine for relapse prevention in ulcerative colitis: A multicenter study. Am J Gastroenterol 1995;90:381–7. Rijk MC, van Lier HJ, van Tongeren JH. Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: A prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study Group. Am J Gastroenterol 1992;87:438 – 42. Levine DS, Riff DS, Pruitt R, et al. A randomized, doubleblind, dose-response comparison of balsalazide 6.75 g, balsalazide 2.25 g, and mesalamine 2.4 g in the treatment of active, mild to moderate ulcerative colitis. Am J Gastroenerol 2002;97:1398 –1407. Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild to moderate ulcerative colitis. Am J Gastroenterol 2002;97:3078 – 86. Kruis W, Schreiber S, Theuer D, et al. Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses. Gut 2001;49:783–9. Green JR, Mansfield JC, Gibson JA, et al. A double-blind comparison of balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or relapsed active ulcerative colitis. Aliment Pharmacol Ther 2002;16:61– 8. Mansfield JC, Giaffer MH, Cann PA, et al. A double-blind comparison of balsalazide, 6.75 g, and sulfasalazine, 3 g, as sole therapy in the management of ulcerative colitis. Aliment Pharmacol Ther 2002;16:69 –77. Green JR, Gibson JA, Kerr GD, et al. Maintenance of remission of ulcerative colitis: A comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator Group. Aliment Pharmacol Ther 1998;12:1207–16. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625–9. Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: Results of a controlled trial. Pentasa Study Group. Am J Gastroenterol 1993;88:1188 –97.
Reprint requests and correspondence: William J. Sandborn, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Received June 26, 2002; accepted Aug. 27, 2002.