Current status and future perspectives on the use of therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel disease

ABSTRACT

Introduction

Despite new treatment options for inflammatory bowel disease (IBD), conventional thiopurines remain a common treatment option for maintaining remission, particularly in non-Westernized countries. Therapeutic drug monitoring (TDM) is advised in standard care for optimizing therapy strategies to improve effectiveness, reveal nonadherence, and reduce toxicity. Still, the rationale of TDM is debated.

Areas covered

Key insights on TDM of thiopurine metabolites are discussed. The pharmacology of thiopurines is described, emphasizing the interindividual differences in pharmacogenetics, pharmacokinetics, and pharmacodynamics. Pharmacological differences between conventional thiopurines and tioguanine are outlined. Finally, several optimization strategies for thiopurine therapy in IBD are discussed.

Expert opinion

TDM has been a useful, but limited, tool to individualize thiopurine therapy. Pharmacokinetic data on the active thiopurine metabolites, derived from measurements in erythrocytes, associated with clinical response only partially predict effectiveness and toxicity. An additional pharmacodynamic marker, such as Rac1/pSTAT3 expression in leukocytes, may improve applicability of TDM in the future.

KEYWORDS:

• 6-TGN
• thiopurines
• therapeutic drug monitoring
• pharmacogenetics
• 6-MMPR
• pharmacology
• inflammatory bowel disease

Article highlights

• The complexity of thiopurine metabolism and the lack of a dose–response relation make therapeutic drug monitoring useful to optimize or individualize thiopurine therapy.

• Therapeutic drug monitoring of thiopurine metabolites is recommended by national and international guidelines to optimize therapy strategies.

• Application of therapeutic drug monitoring of the active thiopurine metabolites 6-TGN and 6-MMPR comprises analytical and biochemical limitations, which should be taken into account when applied to individualize and optimize thiopurine therapy.

• For future perspectives, a pharmacodynamic marker (i.e. Rac1/pSTAT3 expression in leukocytes), in combination with TDM, may be of additional clinical value for prediction of therapeutic effectiveness.

This box summarizes key points contained in the article.

Declaration of interest

AA van Bodegraven served as a speaker, advisor and/or PI for AbbVie, Arendal, ARENA, Cellgene, Ferring, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, BMS, and TEVA and has received research grants from TEVA, Eurostars funding, ZonMW, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.