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

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.

Keywords: 6-MMPR; 6-MP; 6-TGN; 6-TGTP; 6-methylmercaptopurine ribonucleotides; 6-thioguanine nucleotides; 6-thioguanine triphosphate; 95% CI; 95% confidence interval; AZA; Adalimumab; Azathioprine; C-reactive protein; CD; CDAI; CRP; Crohn's disease; Crohn's disease activity index; Drug interaction; HGPRT; HPLC; IBD; IMP; ITPase; MCV; Mercaptopurine; RBC; TDM; TPMT; Therapeutic drug monitoring; UC; azathioprine; high performance liquid chromatography; hypoxanthine-guanine phosphoribosyl transferase; inflammatory bowel disease; inosine monophosphate; inosine triphosphate pyrophosphatase; mean corpuscular volume; mercaptopurine; red blood cells; therapeutic drug monitoring; thiopurine S-methyltransferase; ulcerative colitis.