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

D.R. Wong, M. Pierik, M.L. Seinen, A.A. van Bodegraven, L.P.L. Gilissen, P. Bus, J.A. Bakker, A.A.M. Masclee, C. Neef, L.G.J.B. Engels, P.M. Hooymans

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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. 

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

Keywords

  • 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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