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Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations

Curkovic, Ivanka ; Rentsch, Katharina ; Frei, Pascal ; Fried, Michael ; Rogler, Gerhard ; Kullak-Ublick, Gerd ; Jetter, Alexander

In: European Journal of Clinical Pharmacology, 2013, vol. 69, no. 8, p. 1521-1531

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    Titre
    • Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations
    Auteur
    • Curkovic, Ivanka. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Rentsch, Katharina. Department of Clinical Chemistry, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Frei, Pascal. Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Fried, Michael. Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Rogler, Gerhard. Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Kullak-Ublick, Gerd. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    • Jetter, Alexander. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • European Journal of Clinical Pharmacology, 2013, vol. 69, no. 8, p. 1521-1531. Springer Berlin Heidelberg
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:312547
    Summary
    Purpose: Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine. Methods: A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (<235pmol/8 × 108 erythrocytes) and/or elevated MMPN concentrations (>5,000pmol/8 × 108 erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month. Results: Adequate 6-TGN concentrations were achieved with a combination of 25mg allopurinol and 50mg azathioprine in one patient and with 50mg allopurinol and 50mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 108 erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity. Conclusions: Combination therapy with only 50mg allopurinol and 50mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therapy