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The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients

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Abstract

Background and aims: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline.

The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement.

Methods: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12.

Results: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found.

Conclusions: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine. 

    Research areas

  • Azathioprine, Mercaptopurine, Adalimumab, Drug interaction, Therapeutic drug monitoring, Crohn's disease, INFLAMMATORY-BOWEL-DISEASE, THERAPY, DRUG, 6-MERCAPTOPURINE, AZATHIOPRINE, PHARMACOGENETICS, INFLIXIMAB, IBD
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Details

Original languageEnglish
Pages (from-to)120-128
Number of pages9
JournalJournal of Crohn's & Colitis
Volume8
Issue number2
DOIs
Publication statusPublished - 1 Feb 2014