Relationship Between Azathioprine Dosage and Thiopurine Metabolites in Pediatric IBD Patients

Nguyen, [No Value] Thi-Van-Anh; Vu, Dinh Hoa; Lachaux, Alain; Boulieu, Roselyne

doi:10.1097/ftd.0b013e318282c3a6

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…Only patients with a stable dose of AZA for at least 2 months before measurements of laboratory parameters and clinical records were included to ensure equilibration of treatment . Samples from patients with evidence of poor compliance confirmed by clinicians with total nucleotide levels (6‐TGN + 6‐MeMPN) below 150 pmol/8 × 10 8 RBCs were excluded . Likewise, patients who had received blood transfusions within 3 months were not included.…”

Section: Methodsmentioning

confidence: 99%

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.

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Section: Methodsmentioning

confidence: 99%

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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“…Thiopurine use is associated with dose-dependent adverse drug reactions (ADRs), often leading to dose reduction or drug discontinuation [9]. Hematological toxicity in the form of myelosuppression, secondary to either thiopurine or elevated levels of its metabolite 6-thioguanine (6-TGN), is the most serious ADR.…”

Section: Introductionmentioning

confidence: 99%

Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all?

Walker

Kammermeier

Vora

et al. 2019

aog

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Background Azathioprine is widely used for the maintenance of remission in children with inflammatory bowel disease (IBD). Measuring thiopurine metabolites 6-thioguanine (6-TGN) and 6-methyl-mercaptopurine (6-MMP) can aid in optimizing treatment and preventing toxicity. We report a proactive approach combining early metabolite measurements with IBD activity index to achieve optimal azathioprine dosing. Methods The reporting of azathioprine dosing, IBD activity indexes and thiopurine metabolites was evaluated retrospectively in 40 children with IBD. Additional treatments and the effect of azathioprine on blood counts were also examined. Results Forty children (40% female) with IBD (26 Crohn’s disease, 12 ulcerative colitis, and 2 unclassified IBD), mean age 12.2±3.4 years, were included in the study. The mean azathioprine dose was 1.3±0.4 mg/kg; mean 6-TGN level was 280±151 pmol/8 × 10 8 red blood cells (RBC) and mean 6-MMP level 1022±1007 pmol/8 × 10 8 RBC. Disease activity index (Crohn’s and ulcerative colitis, pediatric specific) at the time of metabolite measurement was 6.5±8. Twenty-eight children did not require azathioprine dose adjustment, while it was increased in 12. Data from children with azathioprine monotherapy were analyzed separately and the results were similar. Conclusion Timely measurement of thiopurine metabolites and clinical assessment can provide a powerful tool to optimize azathioprine dosing and reduce serious adverse effects in children with IBD.

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“…4,15,17,23 In accordance with the conclusion by Osterman et al 16 in a meta-analysis, this study found that higher 6-TGN levels were associated with therapeutic response. Furthermore, the wide interindividual variability in thiopurine metabolism observed in previous studies 14,20,28,30,31 supports the need of treatment individualization based on the metabolite monitoring in clinical settings. Routine testing of metabolites to guide dosing is likely to be promising; yet, conclusion from well-designed prospective studies is still needed.…”

Section: Discussionmentioning

confidence: 63%

“…Because infliximab has been shown to influence metabolite levels 20,21 and an introduction of infliximab during the AZA therapy was part of the criteria for nontherapeutic response to AZA, samples corresponding to the concomitant use of infliximab were also excluded. Measurements of metabolite levels performed after at least 2 months of a stable dose of AZA were included to ensure equilibration of metabolite levels.…”

Section: Data Collectionmentioning

confidence: 99%

Exploring Associations of 6-Thioguanine Nucleotide Levels and Other Predictive Factors with Therapeutic Response to Azathioprine in Pediatric Patients with IBD Using Multilevel Analysis

Nguyen

et al. 2013

Inflammatory Bowel Diseases

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Relationship Between Azathioprine Dosage and Thiopurine Metabolites in Pediatric IBD Patients

Cited by 14 publications

References 41 publications

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all?

Exploring Associations of 6-Thioguanine Nucleotide Levels and Other Predictive Factors with Therapeutic Response to Azathioprine in Pediatric Patients with IBD Using Multilevel Analysis

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