Concentrations of 6-Thioguanine Nucleotide Correlate With Trough Levels of Infliximab in Patients With Inflammatory Bowel Disease on Combination Therapy

doi:10.1016/j.cgh.2014.12.026

Clinical Gastroenterology and Hepatology

Volume 13, Issue 6, June 2015, Pages 1118-1124.e3

https://doi.org/10.1016/j.cgh.2014.12.026 Get rights and content

Background & Aims

In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI).

Methods

We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn’s and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI.

Results

Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10⁸ red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10⁸ RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3–72.5; P < .01).

Conclusions

Although 6-TGN levels of greater than 230 pmol/8 × 10⁸ RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10⁸ RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.

Section snippets

Study Design and Patient Population

We designed a cross-sectional study approved by the University of Miami Miller School of Medicine Institutional Review Board (ID number: 20081100). All subjects provided informed consent. We included all patients with a confirmed diagnosis of CD or ulcerative colitis established by clinical, radiologic, histologic, and/or endoscopic criteria who were receiving maintenance therapy with IFX and AZA/MP. A control group on maintenance therapy with IFX but no thiopurines or methotrexate also was

Results

Seventy-two patients were included. One patient who was being treated with allopurinol and another patient being treated with intermediate TPMT activity were excluded. Four patients receiving 2.5 mg/kg or more of azathioprine had no TPMT enzyme activity available and were assumed to be normal TPMT metabolizers and were included in the study. The baseline characteristics of the study group are shown in Table 1. Of the 72 patients included, 46 had an endoscopic assessment as well as histologic

Discussion

The superiority in outcomes when comparing combination therapy of IFX and thiopurines vs monotherapy with either drug has been well documented.2, 14 At least part of the added efficacy of combination therapy is owing to increased trough levels of the biologic.2, 15 In this study, we found that 6-TGN levels of 125 pmol/8 × 10⁸ RBCs or higher best predicted higher IFX levels and the absence of ATIs; higher 6-TGN concentrations did not confer additional benefit.

Studies have proposed different

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The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
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Citation Excerpt :
In a French study, patients whose dose of azathioprine was reduced to half had similar through levels of infliximab as those with full doses; a level of 6-TGN below 105 pmol/8 × 108 RBC was associated with unfavourable evolution of infliximab pharmacokinetics [25]. Similarly, in a study by Yarur et al, a cut-off of 6-TGN of 125 pmol/8 × 108 RBC predicted better a higher level of infliximab levels [26]. These levels are below the threshold of 235 pmol/8 × 108 RBC associated with clinical efficacy in thiopurine monotherapy [27].
The role of thiopurines in therapeutic algorithms of Crohn's disease (CD) and Ulcerative colitis (UC) is being questioned. This work aimed to investigate current practice and future perspectives of Inflammatory Bowel Disease (IBD) physicians regarding the efficacy, safety, and role of precision medicine with thiopurines in IBD.
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: Conflicts of interest These authors disclose the following: Katherine Drake, Scott Hauenstein, Steven Lockton, and Sharat Singh are employees of Prometheus Laboratories; and Maria Abreu has served as a consultant for AbbVie Laboratories, Prometheus Laboratories, Sanofi Aventis, Takeda, UCB, Pfizer, and Janssen. The remaining authors disclose no conflicts.

: Funding Measurement of thiopurine metabolites and infliximab levels were performed by Prometheus Laboratories (San Diego, CA). Supported by a gift from the Micky & Madeleine Arison Family Foundation Crohn's and Colitis Discovery Laboratory.

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Original articleAlimentary tractConcentrations of 6-Thioguanine Nucleotide Correlate With Trough Levels of Infliximab in Patients With Inflammatory Bowel Disease on Combination Therapy

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Design and Patient Population

Results

Discussion

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Gastroenterology

J Crohns Colitis

J Immunol Methods

Clin Gastroenterol Hepatol

J Crohns Colitis

Gastroenterology

Arch Gerontol Geriatr

Clin Ther

Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis

Am J Gastroenterol

Infliximab, azathioprine, or combination therapy for Crohn's disease

N Engl J Med

Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology

Can J Gastroenterol

Original article
Alimentary tract
Concentrations of 6-Thioguanine Nucleotide Correlate With Trough Levels of Infliximab in Patients With Inflammatory Bowel Disease on Combination Therapy