The influence of adalimumab on thiopurine metabolism in Crohn's disease patients.

The influence of adalimumab on thiopurine metabolism in Crohn’s disease (CD) patients.

Background:
The novel anti–tumor necrosis factor monoclonal antibody adalimumab was significantly superior to placebo for long-term treatment of CD irrespective of concomitant immunosuppressive therapies, including the thiopurines azathioprine (AZA) and 6-mercaptopurine (6-MP). In 2003 Roblin et al. provided evidence for a drug interaction
between infliximab and azathioprine in CD patients.
The mean erythrocyte level of the active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), was comparable before and 3 months after the first infusion, but a significant increase was observed within 1–3 weeks after the first infusion. A mean increase of 50% of the basal level was seen.
An increase of the active thiopurine metabolites, 6-TGN, may on one hand result in a greater efficacy, but on the other hand may result in more (dangerous) adverse events, for instance myelotoxicity.

Objective:
To investigate the influence of adalimumab on the level of the active thiopurine metabolites, 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR), in CD patients treated with a stable maintenance therapy of azathioprine, 6-mercaptopurine or 6-thioguanine (6-TG).

Methods:
CD-patients treated with standard dose AZA (2-2,5mg/kg), 6-MP (1-1,5mg/kg) or 6-TG (10-40mg/day) who require adalimumab for active Crohn’s disease are included prospectively.
Patients receive adalimumab induction therapy with 160mg s.c. (week 0), 80mg s.c. (week 2), and subsequently 40mg s.c. every two weeks.
Efficacy, safety (adverse events), active thiopurine metabolite red blood cell levels and hematological and biochemical safety parameters will be evaluated at week 0 (inclusion), week 2, week 4, week 6 and week 12. The clinical outcome is evaluated by the Crohn’s Disease Acitvity Index (CDAI) at week 0 (inclusion), week 4 and week 12. The duration of the study is twelve weeks. The dose of concomitant medication will be maintained, except for predniso(lo)ne, which can be dosed based on disease activity.

Outcome measures:
The alteration, which means a significant rise or decrease, of 6-TGN and/or 6-MMPR red blood cell levels resulting from concurrent adalimumab therapy.
Efficacy of therapy is evaluated at week 0, week 4 en week 12 by CDAI.
Safety is evaluated by measurement of hematological and biochemical parameters at week 0, 2, 4, 6 and 12 and clinical evaluation.

The novel anti–tumor necrosis factor monoclonal antibody adalimumab was significantly superior to placebo for long-term treatment of CD irrespective of concomitant immunosuppressive therapies, including the thiopurines azathioprine (AZA) and 6-mercaptopurine (6-MP). In 2003 Roblin et al. provided evidence for a drug interaction between infliximab and azathioprine in CD patients. The mean erythrocyte level of the active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), was comparable before and 3 months after the first infusion, but a significant increase was observed within 1–3 weeks after the first infusion. A mean increase of 50% of the basal level was seen. An increase of the active thiopurine metabolites, 6-TGN, may on one hand result in a greater efficacy, but on the other hand may result in more (dangerous) adverse events, for instance myelotoxicity. Objective. To investigate the influence of adalimumab on the level of the active thiopurine metabolites, 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR), in CD patients treated with a stable maintenance therapy of azathioprine, 6-mercaptopurine or 6-thioguanine (6-TG).

Week 0, 2, 4, 6 en 12.

None.