Received on January 23, 2007
Accepted on April 19, 2007

Drug Monitoring and Toxicology

6-Thioguanine Nucleotide-Adapted Azathioprine Therapy Does Not Lead to Higher Remission Rates Than Standard Therapy in Chronic Active Crohn Disease: Results from a Randomized, Controlled, Open Trial

Max Reinshagen ^1*, Ekkehard Schütz, ², Victor W. Armstrong ², Christoph Behrens ³, Christian von Tirpitz ⁴, Andreas Stallmach ⁵, Hans Herfarth ⁶, Jürgen Stein ⁷, Peter Bias ³, Guido Adler ⁴, Maria Shipkova ², Wolfgang Kruis ⁸, Michael Oellerich ², Nicolas von Ahsen ²

¹ Department of Medicine I, Klinikum Braunschweig, Germany
² Department of Clinical Chemistry, University of Göttingen, Germany
³ Clinical Research and Development, Merckle GmbH Ulm, Germany
⁴ Department of Medicine I, University of Ulm, Germany
⁵ Department of Internal Medicine II, Saarland University, Homburg, Germany
⁶ Department of Medicine I, University of Regensburg, Germany
⁷ Department of Medicine I - ZAFES, University of Frankfurt, Germany
⁸ Evangelisches Krankenhaus Kalk, University of Cologne, Germany

^* To whom correspondence should be addressed. E-mail: m.reinshagen{at}klinikum-braunschweig.de.

Background: A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA.

Methods: After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10⁸ erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary).

Results: After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10⁸ Ery were not associated with hepatotoxicity.

Conclusion: Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.