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.

• Authors: 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
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 8 Issue 2 Pg. 120-8 (Feb 2014) ISSN: 1876-4479 [Electronic] England
• PMID: 23932783 (Publication Type: Journal Article)
• Copyright: © 2013.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal, Humanized
• Guanine Nucleotides
• Immunosuppressive Agents
• Thionucleotides
• 6-thioguanylic acid
• Thioinosine
• 6-methylthiopurine ribonucleoside-5'-phosphate
• C-Reactive Protein
• Methyltransferases
• thiopurine methyltransferase
• Hypoxanthine Phosphoribosyltransferase
• Pyrophosphatases
• inosine triphosphatase
• Adalimumab
• Azathioprine

Topics

• Adalimumab
• Adolescent
• Adult
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Azathioprine (metabolism, pharmacokinetics, therapeutic use)
• C-Reactive Protein (metabolism)
• Crohn Disease (drug therapy, metabolism)
• Drug Interactions
• Drug Therapy, Combination
• Erythrocytes (enzymology)
• Female
• Guanine Nucleotides (blood)
• Humans
• Hypoxanthine Phosphoribosyltransferase (blood)
• Immunosuppressive Agents (metabolism, pharmacokinetics, therapeutic use)
• Male
• Methyltransferases (blood)
• Middle Aged
• Prospective Studies
• Pyrophosphatases (blood)
• Severity of Illness Index
• Thioinosine (analogs & derivatives, blood)
• Thionucleotides (blood)
• Young Adult